N-aryl and N-heteroarylurea derivatives as inhibitors of acyl coenzyme A: Cholesterol acyl transferase (ACAT)

ABSTRACT

A compound of the formula ##STR1## and the pharmaceutically acceptable salts thereof, wherein R 17 , R 18  and R 1  are as defined below. The compounds of formula I are inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) and are useful as hypolipidemic and antiatherosclerosis agents.

This application is a 371 of PCT/US93/03539, filed Apr. 20, 1993 whichis a CIP of U.S. application Ser. No. 07/890,050, filed May 28, 1992,now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to new N-aryl and N-heteroarylureaderivatives, pharmaceutical compositions comprising such compounds, andthe use of such compounds to inhibit intestinal absorption ofcholesterol, lower serum cholesterol and reverse the development ofatherosclerosis. The compounds are inhibitors of acyl coenzyme A:cholesterol acyltransferase (ACAT).

Cholesterol that is consumed in the diet (dietary cholesterol) isabsorbed as free cholesterol by the mucosal cells of the smallintestine. It is then esterified by the enzyme ACAT, packaged intoparticles known as chylomicrons, and released into the bloodstream.Chylomicrons are particles into which dietary cholesterol is packagedand transported in the bloodstream. By inhibiting the action of ACAT,the compounds of this invention prevent intestinal absorption of dietarycholesterol and thus lower serum cholesterol levels. They are thereforeuseful in preventing atherosclerosis, heart attacks and strokes.

By inhibiting the action of ACAT, the compounds of the present inventionalso enable cholesterol to be removed from the walls of blood vessels.This activity renders such compounds useful in slowing or reversing thedevelopment of atherosclerosis as well as in preventing heart attacksand strokes.

Other inhibitors of ACAT are referred to in U.S. Pat. Nos. 4,994,465,4,716,175 and 4,743,605 (a divisional of the '175 patent) and in theEuropean Patent Applications having publication numbers 0 242 610, 0 245687, 0 252 524, 0 293 880, 0 297 610, 0 335 374, 0 335 375, 0 386 487, 0399 422, 0 415 123, 0 421 456 and 0 439 059. Additional ACAT inhibitorsare described in PCT publications WO 9015048 and WO 91/04027. Certainureas and thioureas as antiatherosclerosis agents are referred to inU.S. Pat. No. 4,623,662.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein Q is oxygen or sulfur R¹⁷ is --(CH₂)_(n) --(CR¹⁹ R²⁰)_(z)(CH₂)_(r) --Ar XXXVIII

wherein n is 0 or an integer from 1 to 3;

z is 0 or 1;

and r is 0 or an integer from 1 to 4;

R¹⁹ and R²⁰ are independently selected from hydrogen, optionallyhalogenated (C₁ -C₁₂) alkyl, optionally substituted aryl-(C₁ -C₅) alkyl,(C₃ -C₈) cycloalkyl-(C₁ -C₅)alkyl and Ar; or R¹⁹ and R²⁰ and the carbonto which they are attached form a (C₅ -C₇) cycloalkyl ring or abenzene-fused (C₅ -C₇) cyclo-alkyl or -heteroalkyl ring; with theproviso that R¹⁹ and R²⁰ cannot both be hydrogen;

Ar is selected from the group consisting of ##STR3## wherein U is J, adirect bond --CH═CH--or --CH₂ CH₂ --; z, n and r are as defined above; xis an integer from 3 to 10 and w is 0 or an integer from 1 to x-1.

R²¹, R²² and each R²³ is independently selected from the groupconsisting of optionally halogenated (C₁ -C₆)alkyl, optionallyhalogenated (C₁ -C₆)alkoxy, optionally halogenated (C₁ -C₆)alkylthio,phenyl and halogen; wherein the alkyl groups in said alkyl, alkoxy andalthylthio groups may be straight chained or if comprising three or morecarbons may be branched, cyclic or a combination of cyclic and branchedor straight chained moieties;

or R²¹ and R²² together form a group of the formula

    --J(CH.sub.2).sub.t --J--or --(CH.sub.2).sub.q --

wherein J is oxygen or sulfur;

t is an integer from 1 to 3;

and q is an integer from 3 to 5;

K is J--or --CH═CH--;

L is --(CH₂)_(u) or --(CH₂)_(v) J--;

wherein J is as defined above;

u is an integer 3 to 5;

and v is 3 or 4;

R¹⁸ is hydrogen, optionally substituted (C₁ -C₈)alkyl, optionallysubstituted (C₃ -C₈)cycloalkyl, aryl or optionally substituted aryl-(C₁-C₄)alkyl with the proviso that R¹⁸ is hydrogen if any one of n, z or rin formula XXXVIII is not 0;

R¹ is selected from the group consisting of ##STR4## wherein m is asdefined above; n is 0 or 1.

Each I is independently selected from 0 to 3;

Each R⁶ and R¹⁵ is independently selected from the group consisting ofhalogen, (C₁ -C₆)alkyl, (C₁ -C₆) haloalkyl, optionally halogenated (C₁-C₆) alkoxy, optionally halogenated (C₁ -C₆) alkylthio, (C⁵ -C⁷)cycloalkylthio, phenyl (C₁ -C₆)alkylthio, substituted phenylthio,heteroarylthio, heteroaryloxy, (C₁ -C₆)alkylsulfinyl, (C₁ -C₆)alkylsulfonyl, (C₅ -C₇) cycloalkylsulfinyl, (C₅ -C₇) cycloalkylsulfonyl,phenyl (C₁ -C₆) alkylsulfinyl, phenyl (C₁ -C₅) alkylsulfonyl,substituted phenylsulfinyl, substituted phenylsulfonyl,heteroarylsulfinyl, heteroarylsulfonyl, and NR¹⁰ R¹¹, wherein R¹⁰ andR¹¹ are the same or different and are selected from the group consistingof hydrogen, (C₁ -C₆) alkyl, phenyl, substituted phenyl, (C₁ -C₆) acyl,aroyl, and substituted aroyl, wherein said substituted phenyl andsubstituted aroyl groups are substituted with one or more substituentsindependently selected from the group consisting of (C₁ -C₆) alkyl, (C₁-C₆) alkoxy, (C₁ -C₆) alkylthio, halogen and trifluoromethyl, or R¹⁰ andR¹¹, together with the nitrogen to which they are attached, form apiperidine, pyrrolidine or morpholine ring; and

B, D, E and G are selected from the group consisting of nitrogen andcarbon, with the proviso that one or more of B, D and E is nitrogen, andwith the proviso that when G is nitrogen, the group XVI is attached tothe nitrogen of formula I at the 4 or 5 position of the pyrimidine ring(designated by a and b) wherein any of said nitrogens may be oxidized;

or R¹ is ##STR5## wherein R⁷, R⁹ and R⁹ may be the same or different andeach is independently selected from the group consisting of optionallyhalogenated (C₁ -C₅)alkoxy, optionally halogenated (C₁ -C₅)alkylthio,optionally halogenated (C₁ -C₅)alkyl and halogen; with the proviso thatwhen R¹ is a group of the formula XXVII Ar is a group of formula XXXII,XXXIII or XXXV and when Ar is XXXII R¹⁹ or R²⁰ is not alkyl and r informula XXXVIII is 0; or a pharmaceutically acceptable salt of saidcompound.

Unless otherwise indicated, the term "halo", as used herein, includesfluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term "alkyl", as used herein, may bestraight, branched or cyclic, and may include straight and cyclicmoieties as well as branched and cyclic moieties.

Unless otherwise indicated, the term "one or more substituents", as usedherein, refers to from one to the maximum number of substituentspossible based on the number of available bonding sites.

The term "one or more carbons of said non-aromatic ring", as usedherein, refers to from one to all of the carbon atoms that are part ofthe non-aromatic ring of any of the aryl-fused or heteroaryl-fusedsystems described above, and not part of the aromatic ring of saidaryl-fused system.

The term "one or more carbons of said aromatic ring", as used herein,refers to from one to all of the carbon atoms that are part of thearomatic ring of any of the aryl-fused and heteroaryl-fused systemsdescribed above, or are part of both said aromatic and non-aromaticrings of said aryl-fused and heteroaryl-fused system.

The compounds of formula I may have optical centers and therefore mayoccur in different stereoisomeric configurations. The invention includesall stereoisomers of such compounds of formula I, including mixturesthereof.

The present invention also relates to compounds of the formula ##STR6##

wherein R²¹ is (C₁ -C₃) alkyl and R²² is hydrogen or (C₁ -C₃) alkyl.

Preferred compounds of formula I are those wherein R₁ is2,4,6-trifluorophenyl, 2,6-diisopropylphenyl, 2,4-difluorophenyl,6-methoxyquinolin-5-yl, 6-methylquinolin-5-yl,6-methylthioquinolin-5-yl, 6-methoxyisoquinolin-5-yl,6-methylthioisoquinolin-5-yl, 6methylthio-8-acetaminoquinolin-5-yl,4,6-bis(methylthio)pyrimidin-5yl,4,6-bis(methylthio)-2-methylpyrimidin-5-yl,2,4-bis(methylthio)pyridin-3-yl,2,4-bis(methylthio)-6-methylpyridin-3-yl,2,4-bis(ethylthio)-6-methylpyridin-3-yl, 2,4-bis(methylthio)pyridin-3-yland 2,4-bis(isopropylthio)-6-methylpyridin-3-yl.

Specific preferred compounds of formula I are:

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea;

N-[2,4Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,5-dimethylbenzyl)-N'-(indan-2-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,4-dimethylbenzyl)-N'-(indan-2-yl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5yl]-N'-(2,4dimethylbenzyl)-N'-(indan-2-yl)urea;

N-(2,5-Dimethylbenzyl)-N-(indan-2-yl)-N'-(6-methylthioquinolin-5yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2-chlorobenzyl)-N'-(indan-2-yl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(2,5dimethylbenzyl)-N'-(indan-2-yl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(indan-2-yl)-N'-[4-(3-methylbutyl)benzyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-[4-(3-methylbutyl)benzyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(naphth-1-ylmethyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(naphth-2-ylmethyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(4-t-butylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(4-phenylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(naphth-1-ylmethyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(naphth-2-ylmethyl)urea;

N-[2,4-Bis(ethylthio)-6methylpyridin-3-yl]-N'-cycloheptyl-N'-(4-phenylbenzyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(fluoren-2-yl-methyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(naphth-2-ylmethyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-[naphth-2-ylmethyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-(2,4,6-trimethylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'(4-phenylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(fluoren-2-ylmethyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(4-isopropylbenzyl)-N'-(1,2,3,4-tetrahydro-naphth-2-yl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-(3methylbenzo[b]thiophen-2-ylmethyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(1,2,3,4-tetrahydronaphth-2-yl)-N'-(2,4,6-trimethylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(naphth-2-ylmethyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(2,4-dimethylbenzyl)-N'-(indan-2-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(4-isopropylbenzyl)-N'-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(2,4,6-trimethylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(2,4,6-trimethylbenzyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,3-dichlorobenzyl)-N'-(indan-2-yl)urea:

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2,2-diphenylethyl]urea;

N-[2,2-Diphenylethyl)-N'-(6-methylthioquinolin-5-yl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(2,2-diphenylethyl)urea;

N-[4,6-Bis(methylthio)pyrimidin-5-yl]-N'-(2,2-diphenylethyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(1-phenylcyclopentyl)methyl]urea;

N-(6-Methylthioquinolin-5-yl)-N'-[(1-phenylcyclopentyl)methyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclopentyl}methyl]urea;

N-[{1-(4-Methylphenyl)cyclopentyl}methyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-(6-Methylthioquinolin-5-yl)-N'-[(1-phenylcyclohexyl)methyl]urea;

N-[2,4-Bis(methylthio)-methylpyridin-3-yl]-N'-[(1-phenylcyclohexyl)methyl]urea;

N-[{1-(4-Methylphenyl)cyclohexyl}methyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-[{1-(4-methylphenyl)cyclohexyl}methyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclohexyl}methyl]urea;

N-2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea;

N-[2,4-Bis(isopropylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-N'-[(2-ethyl-2-{2-methylphenyl})butyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-N'-[(2-phenyl-2-propyl)pentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-N'-[(2-{2-methylphenyl}-2-propyl)pentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2-methylphenyl}-2-butyl)hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-N'-[(2-{2,5-dimethoxyphenyl}-2-propyl)pentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,3-dimethoxyphenyl}-2-propyl)pentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethylphenyl}-2-propyl)pentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2-methylphenyl)hexyl]urea;

N-[2-(2-Methylphenyl)hexyl]-N'-[6-methylthioquinolin-5-yl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(4-methylphenyl)heptyl]urea;

N-[2-(4-Methylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2-(3-methylphenyl)heptyl]urea;

N-[2-(3-Methylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2-(3-Methylphenyl)heptyl]-N'-(6-methoxyquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)hexyl]urea;

N-[2-(2,5-Dimethylphenyl)hexyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2-(2,5-Dimethylphenyl)hexyl]-N'-(6-methoxyquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5dimethylphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,4-dimethylphenyl)hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,4-dimethylphenyl)heptyl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-2-yl)hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)hexyl]urea;

N-(6-Methylthioquinolin-5-yl)-N'-[2-(naphth-1-yl)hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,3-dimethoxyphenyl)heptyl)-urea;

N-[2-(2,3-Dimethoxyphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)octyl]urea;

N-[2-(3-Methylphenyl)octyl]-N'-(6-methoxyquinolin-5-yl]urea;

N-[2-(3-Methylphenyl)octyl]-N'-(6-methylthioquinolin-5-yl]urea;

N-[2-(Naphth-1-yl)heptyl]-N'-(6-methoxyquinolin-5-yl)urea;

N-[2-(Naphth-1-yl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2-(2,4-Dimethylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea;

N-[2-(2,4-Dimethylphenyl)heptyl]-N'-(6-methoxyquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'2-(3,4,5-trimethoxyphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethyl-4-methoxyphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethoxyphenyl)-phenylbutyl]urea;

N-[2-(2,5-Dimethoxyphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl) urea;

N-[2-(2,5-Dimethoxyphenyl)heptyl-N'-(6-methoxyquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethoxyphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethoxyphenyl)octyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-2-[2-(3-methylphenyl)-6,6,6-trifluorohexyl]urea;

N-[2-(3-Methylphenyl)heptyl]-N'-(6-pentylthioquinolin-5-yl)urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-{2-(5-chlorobenzo[b]thiophen-3-yl)heptyl}urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)octyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[5-methyl-2-{3-methylphenyl}hexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethylphenyl}-4-phenylbutyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,6-dimethylphenyl)-5-phenylpentyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)-6-methylheptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)-6-methylheptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-methylheptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)heptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-phenylhexyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,4,6-trimethylphenyl)octyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6,6,6-trifluorohexyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]urea;

N-[2-(2,5-Dimethylphenyl)heptyl]-N'-[6-methylthioquinolin-5-yl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-methylheptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-5-phenylpentyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)octyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2,5-dimethylphenyl)octyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2,5-dimethylphenyl)-5-methylhexyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2chlorobenzo[b]thiophen-3yl)6-methylheptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2chlorobenzo[b]thiophen-3-yl)-5-methylhexyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(5,6,7,8-tetrahydronaphth-1-yl)heptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)heptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)octyl]urea;

N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethyl-4-methoxyphenyl)heptyl]urea;

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea;

N-[2-(2-Chlorobenzo[b]thiophen-3-yl)-5-methylhexyl]-N'-(2,6-diisopropyl)urea;

N-(2,6-Diisopropylphenyl)-N'-[2-(5-methylbenzo[b]thiophen-3-yl-5-methylhexyl]urea;

N-[2-(Benzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[2-(Benzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[2-(2-Chiorobenzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea;

N-(2,6-Diisopropylphenyl)-N'-[2-(5-methylbenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]urea;

N-[2-(2-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]-N'-(2,6-diisopropylphenyl)urea;

N-(2,6-Diisopropylphenyl)-N'-[2-(naphth-2-yl)-6,6,6-trifluorohexyl]urea;

N-[7,7-Difluoro-2-(naphth-1-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[7,7-difluoro-2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[2-(5-Chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[2-(2-Chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-[2-(5-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]-N'-(2,6-diisopropylphenyl)urea;

N-(2,6-(Diisopropylphenyl)-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea;

N-[2-(5-Chlorobenzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea;

N-(2,6-(Diisopropylphenyl)-N'-[2-(2,5-dimethylphenyl)-6,6,6-trifluorohexyl]urea;

N-[7,7-Difluoro-2-(2,5-dimethylphenyl)heptyl]-N'-(2,6-diisopropylphenyl)urea;

N-(2,6-Diisopropylphenyl)-N'-[2-(napth-1-yl)heptyl]urea;

and

N-(2,6-Diisopropylphenyl)-N'-[6-methyl-2-(napth-1-yl)heptyl]urea.

The present invention also relates to all radiolabelled forms of thecompounds of the formulae I, II and XXVIII. Such radiolabelled compoundsare useful as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays in both animals and man.

The present invention also relates to a pharmaceutical composition forinhibiting ACAT, inhibiting intestinal absorption of cholesterol,reversing or slowing the development of atherosclerosis, or lowering theconcentration of serum cholesterol in a mammal, including a human,comprising an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, effective in inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol in a mammal, including a human, comprisingadministering to a mammal an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, effective in inhibiting ACAT,inhibiting intestinal absorption of cholesterol, reversing or slowingthe development of atherosclerosis, or lowering the concentration ofserum cholesterol.

Examples of pharmaceutically acceptable acid addition salts of thecompounds of formula I salts are the salts of hydrochloric acid,p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid,salicyclic acid, oxalic acid, hydrobromic acid, phosphoric acid,methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, andmandelic acid.

DETAILED DESCRIPTION OF THE INVENTION

The reaction scheme below illustrates the synthesis of certain5-aminoquinolines and 5-aminoisoquinolines used in the practice of thisinvention.

Except where otherwise stated, Q, R¹, R⁶, R⁷, R⁸, R⁹, R¹⁵, R¹⁷, R¹⁸, n,m, o, p, A, B, D, E and G in the reaction schemes and discussion thatfollows are defined as above. ##STR7##

The aminopyrimidine and aminopyridine intermediates used in the presentinvention are known in the literature or may be prepared by methodsknown in the art from intermediates that are known in the literature orcommercially available. References for the preparation of many of thepyrimidine and pyridine intermediates can be found in the monographs"The Pyrimidines", ed. by D. J. Brown (1962) and "Pyridine and itsDerivatives", ed. by R. A. Abramovitch (1961), Interscience Publishers,Inc., New York, N.Y., and their supplements. The preparation of certainof these intermediates is described in greater detail below.

2,6-Disubstituted-5-amino-pyrimidine derivatives may be prepared byreacting the appropriately substituted 4,6-dihydroxypyrimidine with anitrating agent such as fuming nitric acid in acetic acid at atemperature from about 15° C. to about 40° C. for a period of about 1 toabout 5 hours. The resulting 5-nitropyrimidines are converted to the2,4-dichloro-5-nitropyrimidine intermediates using a chlorinating agentsuch as phosphoryl chloride, alone or in the presence of a base,preferably diethylaniline, at a temperature from about 100 to about 115°C. for a period of about 0.5 to about 2 hours. Procedures for carryingout these transformations are described in J. Chem. Soc., 3832 (1954).

The 2,6-bis(alkylthio)-5-nitropyrimidine derivatives may be prepared byreacting the appropriate dichloro intermediate with two equivalents ofsodium alkylthiolate in a solvent such as dimethylformamide or,preferably, methanol, for about 4 to about 16 hours at a temperaturefrom about 0 to about 30° C., preferably at ambient temperature.Monosubstitution of the dichloro intermediate is accomplished by usingone equivalent of nucleophile, at a reaction temperature of about 0 toabout 100° C., depending on the reactivity of the nucleophile, in aninert solvent such as dimethyl-formamide or tetrahydrofuran, for aperiod of about 4 to about 16 hours.

The resulting monochloro derivative is then reacted with one equivalentof a different nucleophile to yield a disubstituted derivative withdifferent substituents on the carbon atoms at positions 2 and 4. The2,6-disubstituted-5-nitropyrimidine is reduced using a reducing agentsuch as stannous chloride in concentrated hydrochloric acid or hydrogengas with an appropriate catalyst, to yield the corresponding5-aminopyrimidine derivative.

The novel pyridines of formula XXVIII and other2,4-disubstituted-3-aminopyridine derivatives may be prepared byreacting the appropriate 2,4-dihydroxypyridine with a nitrating agentsuch as concentrated nitric acid at 80-100° C. for 15-60 minutes. Forexample, the preparation of 2,4-dihydroxy-6-methyl-3-nitropyridine isdescribed in J. Heterocyclic Chem., 1970, 7, 389. The resulting2,4-dihydroxy-3-nitro-pyridine is sequentially converted to the2,4-dichloro-3-nitropyridine, 2,4-disubstituted-3-nitro-pyridine and2,4-disubstituted-3-aminopyridine derivatives, using reaction conditionssimilar to those described above for the pyrimidine series.

The preparation of certain 5-aminoquinolines and 5-aminoisoquinolines isillustrated in scheme 1. Referring to scheme 1, 5-aminoquinolines andisoquinolines of the formulae XV and XVII may be prepared as follows. Aquinoline or isoquinoline of the formula XIII is nitrated at the 5position, respectively, by reacting it with a nitrating agent such asnitric acid or potassium nitrate with or without an acid catalyst suchas sulfuric acid, for from about 2 to 16 hours at a temperature fromabout 0-100° C. The nitro compound of formula XIV so formed is thenreduced using a reducing agent such as stannous chloride, iron, zinc, orhydrogen gas with an appropriate catalyst, with or without an acidcatalyst such as hydrochloric acid, for from about 2 to 16 hours at atemperature from about 0-100° C., to yield the corresponding5-aminoquinoline or 5-aminoisoquinoline of formula XV.

Compounds of the formula XVII, wherein R¹⁵ is --SR¹⁴ and is attached tothe quinoline or isoquinoline ring at the 6 position, and wherein R¹⁴ is(C₁ -C₆)alkyl, (C₅ -C₇) cycloalkyl, phenyl (C₁ -C₄) alkyl, phenyl,substituted phenyl, heteroaryl, or substituted heteroaryl, may beprepared as follows. A compound of the formula XIV, wherein R⁵ is --Cland is attached to the quinoline or the isoquinoline ring at the 6position, is reacted with a compound of the formula R¹⁴ SH, wherein R¹⁴is as defined above, and a base such as sodium hydride, or such compoundof the formula XIV is reacted with a compound of the formula R¹⁴ SNa,wherein R¹⁴ is as defined above, in an inert solvent such astetrahydrofuran, for about 4 to 16 hours at a temperature of from about-10° C. to room temperature. The preferred temperature is -10° C. Thisreaction yields a compound of the formula XVI, which is then convertedto the corresponding 5-aminoquinoline or isoquinoline of the formulaXVII by the method described above for reduction of compounds of formulaXIV.

Treatment of the compound of formula R¹⁷ R¹⁸ NH with a compound of theformula R¹ N═C═Q yields the corresponding urea (Q═O) or thiourea (Q═S)of the formula I. Procedures for the preparation of compounds of theformula R¹ N═C═Q are known in the literature and several methods arereviewed in "Organic Functional Group Preparations, Vol 1", Chapter 12,Academic Press, New York (1968). The preparation of ureas and thioureasby the reaction of amines with isocyanates and isothiocyanates,respectively, are reviewed in Organic Functional Group Preparations,Vol. 2, Chapter 6, Academic Press, New York (1971).

Compounds of the formula R¹ N═C═O may be obtained by reacting compoundof the formula R¹ NH₂ with 1 to 6 equivalents of an appropriate reagentsuch as phosgene, trichloromethyl chloroformate orbis(trichloromethyl)carbonate. The reaction is generally carried out inan inert ether, aromatic hydrocarbon or chlorinated hydrocarbon solventsuch as dioxane, diisopropyl ether, benzene, toluene, dichloromethane orchloroform. It may be conducted in the presence of a base such as atertiary amine (e.g., pyridine, triethylamine or quinoline). Reactiontemperatures may range from about 0° C. to about 120° C., and arepreferably from about 20° C. to about 100° C. Preferably, theheterocyclic amine of formula R¹ NH₂ is reacted with 1 to 2 equivalentsof trichloromethyl chloroformate in refluxing dichloromethane for about18 hours.

The reaction of compounds of the formula R¹ N═C═Q with compounds offormula R¹⁷ R¹⁸ NH to form compounds of the formula I is carried out inan inert, anhydrous solvent such as chloroform, benzene,dimethylformamide, dioxane or tetrahydrofuran, at a temperature fromabout 20° C. to 100° C., for about 3 to 30 hours, preferably indimethylformamide at about 80° C. for about 16 hours.

Amines of the formula NHR¹⁷ R¹⁸ may be prepared by a variety of methodswell known in the art (see e.g., Vogel's Textbook of Practical OrganicChemistry, Longman, Inc., New York, pp. 769-782 and pp. 717-718 (5th ed.1989), Organic Functional Group Preparations, Vol 2. Academic Press, NewYork, pp. 401-405 (2nd ed. 1983). Other examples of methods for thepreparation of amines of the formula NHR¹⁷ R¹⁸ are described in EP 0399422 A1, EP 0415 123 A2 and EP 0439 059 A2.

For instance, compounds of the formula R¹⁷ R¹⁸ NH wherein R¹⁹ ishydrogen and R²⁰ is optionally substituted aryl-(C₁ -C₆)alkyl oroptionally halogenated (C₁ -C₁₂) alkyl may be prepared by treating acompound of the formula Ar--CH₂ --CN with an alkali metal amide followedby addition of a compound of the formula R²⁰ I to form a compound of theformula ##STR8## which is subsequently reduced to the amine of theformula ##STR9## by standard means.

The alkali metal moieties of the amides may be exemplified by lithium,sodium and potassium, preferably lithium. A most preferred amide islithium diisopropylamide.

The reduction of the nitrites may be effected using borane, e.g. in theform of its complex with tetrahydrofuran, or by hydrogenation in thepresence of Raney nickel.

Except where otherwise noted, pressure is not critical in any of theabove reactions. Preferred temperatures for the above reactions werestated where known. In general, the preferred temperature for eachreaction is the lowest temperature at which product will be formed. Thepreferred temperature for a particular reaction may be determined bymonitoring the reaction using thin layer chromatography.

Preparation of certain novel intermediates useful in preparing thecompounds of the invention is described in preparative examples Athrough R.

The novel compounds of formula I and the pharmaceutically acceptablesalts thereof are useful as inhibitors of acyl coenzyme A: cholesterolacyltransferase (ACAT). As such they inhibit intestinal absorption ofcholesterol in mammals and are useful in the treatment of high serumcholesterol in mammals, including humans. As used herein, treatment ismeant to include both the prevention and alleviation of high serumcholesterol. The compound may be administered to a subject in need oftreatment by a variety of conventional routes of administration,including orally, parenterally and topically. In general, thesecompounds will be administered orally or parenterally at dosages betweenabout 0.08 and about 30 mg/kg body weight of the subject to be treatedper day, preferably from about 0.08 to 5 mg/kg. For an adult human ofapproximately 70 kg of body weight, the usual dosage would, therefore,be about 5.6 to about 2100 mg per day. However, some variation in dosagewill necessarily occur depending on the condition of the subject beingtreated and the activity of the compound being employed. The personresponsible for administration will, in any event, determine theappropriate dose for the individual subject.

A compound of formula I or a pharmaceutically acceptable salt thereofmay be administered alone or in combination with pharmaceuticallyacceptable carriers, in either single or multiple doses. Suitablepharmaceutical carriers include inert solid diluents or fillers, sterileaqueous solutions and various organic solvents. The resultingpharmaceutical compositions are then readily administered in a varietyof dosage forms such as tablets, powders, lozenges, syrups, injectablesolutions and the like. These pharmaceutical compositions can, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus, for purposes of oral administration,tablets containing various excipients such as sodium citrate, calciumcarbonate and calcium phosphate may be employed along with variousdisintegrants such as starch, alginic acid and certain complexsilicates, together with binding agents such as polyvinylpyrrolidone,sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortabletting purposes. Solid compositions of a similar type may also beemployed as fillers in soft and hard filled gelatin capsules. Preferredmaterials for this include lactose or milk sugar and high molecularweight polyethylene glycols. When aqueous suspensions or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes and, if desired, emulsifying or suspending agents,together with diluents such as water, ethanol, propylene glycol,glycerin and combinations thereof.

For parenteral administration, solutions of a compound of formula I or apharmaceutically acceptable salt thereof in sesame or peanut oil,aqueous propylene glycol, or in sterile aqueous solution may beemployed. Such aqueous solutions should be suitably buffered ifnecessary and the liquid diluent first rendered isotonic with sufficientsaline or glucose. Such solutions are especially suitable forintravenous, intramuscular, subcutaneous and intraperitonealadministration. In this connection, the sterile aqueous media employedare all readily available by standard techniques known to those skilledin the art.

The activity of the compounds of the present invention as ACATinhibitors may be determined by a number of standard biological orpharmacological tests. For example, the following procedure was used todetermine the ACAT inhibiting activity of compounds of formula I. ACATwas assayed in microsomes isolated from chow fed Sprague-Dawley ratsaccording to Bilheimer, J. T., Meth. Enzymol., 111, ps 286-293 (1985),with minor modifications. Microsomes from rat liver were prepared bydifferential centrifugation and washed with assay buffer prior to use.The assay mixture contained 25 μl of BSA (40 mg/ml), 30 μl of rat livermicrosome solution (100 μg microsomal protein), 20 μl of assay buffer(0.1 M K₂ PO₄, 1.0 mM reduced Glutathione, pH 7.4), 20 μg of cholesterolin 100 μl of a 0.6% Triton WR-1339 solution in assay buffer, and 5 μl oftest compound dissolved in 100% DMSO (total volume=180 μl). The assaymixture was incubated for 30 min at 37° C. The reaction was started bythe addition of 20 μl of ¹⁴ C-Oleoyl-CoA solution (1000μM, 2,000dpm/nmol) and run for 15 min at 37° C. The reaction was stopped by theaddition of 1 ml EtOH. The lipids were extracted into 4 ml hexane. A 3ml aliquot was dried under N₂, and resuspended in 100 μl of chloroform.50 μl of chloroform were spotted on a heat activated TLC plate anddeveloped in hexane: diethyl ether: acetic acid (85:15:1, v:v:v).Incorporation of radioactivity into cholesteryl esters was quantified ona Berthold LB2842 Linear TLC Analyzer. ACAT inhibition was calculatedrelative to a DMSO control assay.

The activity of the compounds of formula I in inhibiting intestinalabsorption of cholesterol may be determined by the procedure of Melchoirand Harwell, J. Lipid. Res. 26, 306-315 (1985).

The present invention is illustrated by the following examples. It willbe understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹ H NMR) and ¹³ C nuclearmagnetic resonance spectra (¹³ C NMR) were measured for solutions indeuterochoroform (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;q, quintet; hx, hextet; h, heptet, m, multiplet; br, broad; vb, verybroad; c, complex.

PREPARATION OF INTERMEDIATES Preparative Example A5-Iodo-1,1-difluoropentane

A solution of 5-bromo-1,1-difluoropentane (2.65 g, 14.2 mmol) and sodiumiodide (10.63 g, 70.8 mmol) in acetone (150 ml) was refluxed undernitrogen overnight. The reaction mixture was then filtered and thefiltrate was concentrated at atmospheric pressure. The residue wasdissolved in dichloromethane (50 ml) and the solution was washed withwater (2×30 ml) and brine (30 ml), dried (sodium sulfate) andconcentrated under reduced pressure at room temperature. The crudeproduct was distilled under reduced pressure to yield the title compoundas a yellowish liquid (2.24 g, 93% yield), bp 73-75° C., 10 mm Hg. ¹ HNMR (300 MHz, CDCl₃) δ1.59 (m, 2H), 1.84 (c, 4H), 3.2 (t, 2H), 5.63,5.82, 6.01 (3t, total 1H).

Preparative Example B 2-(2-Chlorobenzo[b]thiophen-3-yl)-7,7-difluoroheptanenitrile

A solution of lithium diisopropylamide in cyclohexane (5.13 mmol, 3.42ml of a 1.5M solution) was added dropwise to a solution of(2-chlorobenzo[b]thiophen-3-yl)acetonitrile (1.06 g, 5.13 mmol) intetrahydrofuran (10 ml) cooled to -70° C. under nitrogen. The resultingsolution was stirred at -70° C. for 20 min, then a solution of5-iodo-1,1-difluoropentane (1.2 g, 5.13 mmol) in tetrahydrofuran (5 ml)was slowly added at -70° C. The reaction mixture was stirred at -70° C.for 1 hr, then slowly allowed to warm to room temperature and left atthat temperature overnight. Water (60 ml) was added to the reactionsolution and the resulting mixture was extracted with ethyl acetate(3×70 ml). The combined ethyl acetate extracts were washed with brine(80 ml), dried (sodium sulfate) and concentrated in vacuo. The crudeproduct (2.1 g) was purified by column chromatography on silica gel (200g), eluting with 4:1 hexane/dichloromethane followed by 7:3hexane/dichloromethane to yield the title compound as an oil (950 mg,59% yield). ¹ H NMR (300 MHz, CDCl₃) δ1.4-1.7 (c, 4H), 1.7-2.05 (c, 3H),2.2 (c, 1H) 4.3 (t, 1H), 5.6, 5.78, 5.98 (3t, total 1H), 7.42 (m, 2H),7.75 (d, 1H), 7.95 (d, 1H).

In a similar manner, the following nitriles were synthesized:

Preparative Example C 2-(naphth-1-yl)-7,7-difluoroheptanenitrile

75% yield

¹ H NMR (300 MHz, CDCl₃) δ1.44-1.72 (c, 4H), 1.72-1.94 (c, 2H), 2.07 (m,2H), 4.57 (t, 1H), 5.6, 5.8, 5.99 (3t, total 1H), 7.44-7.64 (m, 3H),7.69 (d, 1H), 7.9 (m, 3H).

Preparative Example D 2-(2,5-Dimethylphenyl)-6-phenylhexanenitrile

86% yield

¹ H NMR (300 MHz, CDCl₃) δ1.48-2.0 (c, 6H), 2.28 (s, 3H), 2.34 (s, 3H),2.63 (t, 2H), 3.89 (q, 1H), 7.06 (m, 2H), 7.12-7.32 (m, 6H)

Preparative Example E 2-(2-Chlorobenzo[b]thiophen-3-yl-7,7-difluoroheptanamine

A solution of borane-tetrahydrofuran complex in tetrahydrofuran (6.07mmol, 6.07 ml of a 1.0M solution) was added dropwise to a solution of(2-chlorobenzo[b]thiophen-3-yl)-7,7-difluoroheptanenitrile (950 mg, 3.03mmol) in tetrahydrofuran (15 ml) at room temperature under nitrogen andthe reaction was left at room temperature overnight. Aqueoushydrochloric acid (5 ml of a 3N solution) was then added and reactionmixture was refluxed for 30 min followed by removal of thetetrahydrofuran in vacuo. The resulting aqueous phase was diluted withwater (10 ml) and extracted with ethyl acetate (3×30 ml). The combinedethyl acetate extracts were washed with brine (40 ml), dried (sodiumsulfate) and concentrated in vacuo. The residue (930 mg) was purified bycolumn chromatography on silica gel (100 g) eluting with 9:1 ethylacetate/methanol to yield the title compound as an oil (632 mg, 66%yield).

In a similar manner, the following amines were synthesized:

Preparative Example F[2-(2-Chlorobenzo[b]thiophen-3-yl)-5-methylhexanamine

67% yield

¹ H NMR (300 MHz, CDCl₃) δ0.79, 0.80, 0.81, 0.83 (2d, 6H), 0.92-1.08 (m,1H), 1.1-1.28 (m, 1H), 1.5 (h, 1H), 1.66 (b, 2H), 1.78 (m, 1H), 1.94 (c,1H), 3.09 (m, 1H), 3.18-3.37 (c, 2H), 7.32 (c, 2H), 7.71 (c, 1H), 7.79(c, 1H).

Preparative Example G 5-Methyl-2-(5-methylbenzo[b]thiophen-3-yl)hexanamine

53% yield

¹ H NMR (300 MHz, CDCl₃) δ0.84 (d, 6H), 1.18 (c, 2H), 1.52 (h, 1H), 1.75(bq, 2H), 2.02 (b, 2H), 2.49 (s, 3H), 3.0 (d, 2H), 3.12 (p, 1H), 7.1 (s,1H), 7.17 (d, 1H), 7.59 (s, 1H), 7.73 (d, 1H).

Preparative Example H 2-(Benzo[b]thiophen-3-yl)heptanamine

65% yield

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.25 (c, 6H), 1.76 (c, 2H), 2.05(b, 2H), 3.03 (c, 2H), 3.19 (p, 1H), 7.14 (s, 1H), 7.36 (c, 2H), 7.81(m, 1H), 7.87 (m, 1H).

Preparative Example I 2-(Benzo[b]thiophen-3-yl)-6-methylheptanamine

66% yield

¹ H NMR (300 MHz, CDCl₃) δ0.78, 0.80, 0.81, 0.82 (2d, 6H), 1.1-1.44 (c,4H), 1.47 (h, 1H), 1.74 (q, 2H), 2.06 (b, 2H), 3.04 (c, 2H), 3.19 (p,1H), 7.14 (s, 1H), 7.36 (c, 2H), 7.84 (m, 2H).

Preparative Example J 2-(5-Methylbenzo[b]thiophen-3-yl)-6,6,6trifluorohexanamine

51% yield

¹ H NMR (300 MHz, CDCl₃) δ1.54 (m, 2H), 1.69 (b, 2H), 1.86 (c, 2H), 2.06(m, 2H), 2.49 (s, 3H), 3.03 (d, 2H), 3.16 (p, 1H), 7.12 (s,1H), 7.19 (d,1H), 7.57 (s, 1H), 7.75 (d, 1H).

Preparative Example K2-(2-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexanamine

60% yield

¹ H NMR (300 MHz, CDCl₃) δ1.35-1.7 (c, 4H), 1.89 (c, 1H), 2.05 (c, 3H),3.09 (q, 1H), 3.2-3.4 (c, m, 2H), 7.34 (m, 2H), 7.75 (m, 2H).

Preparative Example L 2-(2-Chlorobenzo [b]thiophen-3-yl)heptanamine

68% yield

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.2 (c, 6H), 1.65 (b, 2H), 1.78(c, 1H), 1.95 (c, 1H), 3.07 (q, 1H), 3.16-3.38 (c, m, 2H), 7.32 (c, 2H),7.72 (m, 1H), 7.8 (m, 1H).

Preparative Example M 2-(5-Chlorobenzo[b]thiophen-3-yl)heptanamine

60% yield

¹ H NMR (300 Mhz, CDCl₃) δ0.84 (t, 3H), 1.26 (c, 6H), 1.65-1.9 (c, 4H),3.0 (d, 2H), 3.1 (p, 1H), 7.19 (s, 1H), 7.29, 7.30, 7.32, 7.33 (q, 1H),7.77 (m, 2H).

Preparative Example N 2-(5-Methylbenzo[b]thiophen-3-yl)heptanamine

63% yield

¹ H NMR (300 MHz, CDCl₃) δ0.84 (t, 3H), 1.26 (c, 6H), 1.76 (c, 2H), 1.84(b, 2H), 2.49 (s, 3H), 3.0 (d, 2H), 3.13 (p, 1H), 7.1 (s, 1H), 7.18 (d,1H), 7.6 (s, 1H), 7.74 (d, 1H).

Preparative Example O2-(5-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexanamine

33% yield

¹ H NMR (300 MHz, CDCl₃) δ1.43-2.0 (c, 6H), 2.08 (m, 2H), 3.02 (c, 2H),3.12 (m, 1H), 7.22 (s, 1H), 7.31, 7.32, 7.34, 7.35 (q, 1H), 7.75, 7.76,7.77, 7.8 (q, 2H).

Preparative Example P2-(5-Chlorobenzo[b]thiophen-3-yl)-6-methylheptanamine

69% yield

¹ H NMR (300 MHz, CDCl₃) δ0.79, 0.81, 0.82, 0.83 (2d, 6H), 1.1-1.33 (c,4H), 1.47 (h, 1H), 1.62-1.93 (c, 4H), 3.01 (d, 2H), 3.11 (p, 1H), 7.2(s, 1H) 7.29, 7.30, 7.32, 7.33 (q, 1H), 7.76, 7.77, 7.78, 7.784 (q, 2H).

Preparative Example Q 2-(Naphth-1-yl)-7,7-difluoroheptanamine

A mixture of 2-(naphth-1-yl)-7,7-difluoroheptanenitrile (413 mg, 1.51mmol), Raney nickel (413 mg) and ammonia (0.9 g) in methanol (20 ml) washydrogenated under 340 kPa (50 psi) hydrogen overnight at roomtemperature. The mixture was filtered and the filtrate was concentratedin vacuo. The residue was partitioned between ethyl acetate (50 ml) andwater (40 ml) and the ethyl acetate extract was washed with brine (30ml), dried (sodium sulfate) and concentrated in vacuo. The residue (400mg) was purified by column chromatography on silica gel (100 g), elutingwith 85:15 ethyl acetate/methanol to yield the title compound as an oil(321 mg, 77% yield). ¹ H NMR (300 MHz, CDCl₃) δ1.35 (c, 6H), 1.78 (c,4H), 3.08 (c, 2H), 3.61 (c, 1H), 5.52, 5.71, 5.9 (3t, total 1H), 7.37(d, 1H), 7.5 (m, 3H), 7.75 (d, 1H), 7.88 (d, 1H), 8.16 (d, 1H).

The following compound was synthesized in a similar manner:

Preparative Example R 2-(2,5-Dimethylphenyl)-6-phenylhexanamine

74% yield

¹ H NMR (300 MHz, CDCl₃) δ1.15-1.44 (c, 4H), 1.5-1.75 (c, 4H), 2.29 (s,3H), 2.32 (s, 3H), 2.55 (m, 2H), 2.9 (c, 3H), 6.91, 6.94, 6.95 (t, 2H),7.05 (d, 1H), 7.14 (m, 3H), 7.29 (t, 2H).

EXAMPLE 1N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea

A solution of 2-(4-isopropylbenzylamino)indane (159 mg, 0.6 mmol) and2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (136 mg, 0.6 mmol)in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight.The reaction mixture was cooled to room temperature, diluted with 50 mlethyl acetate and washed with 3×50 ml water, then 50 ml brine, dried(sodium sulfate), filtered and concentrated in vacuo. The solid residue(265 mg) was purified by column chromatography on silica gel (150 g),eluting with 7:3 hexane/ethyl acetate to yield the title compound as awhite solid (195 mg, 66% yield).

¹ H NMR (300 MHz, CDCl₃ δ1.25 (d, 6H), 2.36 (s, 3H), 2.45 (s, 3H), 2.47(s, 3H), 2.91 (h, 1H), 3.06 (dd, 2H), 3.31 (dd, 2H), 4.57 (s, 2H), 5.39(p, 1H), 5.57 (s, 1H), 6.59 (s, 1H), 7.15 (c, 4H), 7.22-7.35 (m, 4H).

The 1- and indan-2-yl urea derivatives of Examples 2-18 were synthesizedin a similar manner.

EXAMPLE 2N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,5-dimethylbenzyl)-N'-(indan-2-yl)urea

66% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.15 (s, 3H), 2.37 (s, 3H), 2.39 (s, 3H), 2.45(s, 3H), 2.47 (s, 3H), 2.99 (dd, 2H), 3.29 (dd, 2H), 4.47 (s, 2H), 5.48(s) and 5.50 (m) (total 2H), 6.58 (s, 1H), 7.04 (m, 2H), 7.15 (c, 5H),7.43 (s, 1H).

EXAMPLE 3N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,4-dimethylbenzyl)-N'-(indan-2-yl)urea

66% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.17 (s, 3H), 2.33 (s, 3H), 2.37 (s, 3H), 2.45(s, 3H), 2.48 (s, 3H), 2.99 (dd, 2H), 3.26 (dd, 2H), 4.48 (s, 2H), 5.44(m) and 5.49 (s) (total 2H), 6.58 (s, 1H), 6.99 (s, 1H), 7.14 (c, 5H),7.47 (d, 1H).

EXAMPLE 4N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea

62% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.25 (d, 6H), 2.46 (s, 6H), 2.56 (s, 3H), 2.92(h, 1H), 3.04 (dd, 2H), 3.31 (dd, 2H), 4.55 (s, 2H), 5.41 (m) and 5.46(s) (total 2H), 7.16 (c, 4H), 7.23-7.34 (m, 4H).

EXAMPLE 5N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(2,4-dimethylbenzyl)-N'-(indan-2-yl)urea

70% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.17 (s, 3H), 2.33 (s, 3H), 2.47 (s, 6H), 2.56(s, 3H), 2.99 (dd, 2H), 3.28 (dd, 2H), 4.46 (s, 2H), 5.41 (s) and 5.44(m) (total 2H), 6.9 (m, 1H), 7.14 (c, 5H), 7.44 (d, 1H).

EXAMPLE 6N-(2,5-Dimethylbenzyl)-N-(indan-2-yl-N'-(6-methylthioquinolin-5-yl)urea

19% yield. ¹ H NMR (300 MHz, CDCl₃) δ2.20 (s, 3H), 2.45 (s, 6H), 3.06(dd, 2H), 3.34 (dd, 2H), 4.60 (s, 2H), 5.54 (p, 1H), 6.20 (s, 1H), 7.07(m, 2H), 7.16 (c, 4H), 7.38 (1, 1H), 7.46 (s, 1H), 7.60 (d, 1H), 7.96(d, 1H), 8.07 (d, 1H), 8.82 (m, 1H).

EXAMPLE 7N-[2,4-Bis-methylthio)-6-methylpyridin-3-yl]-N'-(2-chlorobenzyl)-N'-(indan-2-yl)urea

17% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.38 (s, 3H), 2.45 (s, 3H), 2.48 (s, 3H), 3.02(dd, 2H), 3.26 (dd, 2H), 4.67 (s, 2H), 5.37 (p, 1H), 5.51 (s, 1H), 6.59(s, 1H). 7.14 (q, 4H), 7.25 (c, 1H), 7.38 (c, 2H), 7.64 (d, 1H).

EXAMPLE 8N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(2,5-dimethylbenzyl-N'-(indan-2-yl)urea

69% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.15 (s, 3H), 2.39 (s, 3H), 2.47 (s, 6H), 2.57(s, 3H), 2.98 (dd, 2H), 3.29 (dd, 2H), 4.45 (s, 2H), 5.40 (s, 1H), 5.50(p, 1H), 7.06 (m, 2H), 7.14 (m, 4H), 7.38 (s, 1H).

EXAMPLE 9N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(indan-2-yl)-N'-[4-(3-methylbutyl)benzyl]urea

71% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.93 (d, 6H), 1.45-1.69 (c, 3H), 2.47 (s, 6H),2.57 (s) and 2.61 (m) (total 5H), 3.03 (dd, 2H), 3.31 (dd, 2H), 4.55 (s,2H), 5.40 (m) and 5.46 (m) (total 2H), 7.10-7.33 (c, 8H).

EXAMPLE 10N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-[4-(3-methylbutyl)benzyl]urea

30 58% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.92 (d, 6H), 1.44-1.68 (c, 3H), 2.36 (s, 3H),2.44 (s, 3H), 2.46 (s, 3H), 2.60 (m, 2H), 3.04 (dd, 2H), 3.30 (dd, 2H),4.56 (s, 2H), 5.39 (p, 1H), 5.54 (s, 1H), 6.58 (s, 1H), 7.10-7.34 (c,8H).

EXAMPLE 11N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(naphth-1-ylmethyl)urea

25% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.1 (c, 1H), 2.32-2.54 [total 10H, including2.4 (s, 3H), 2.46 (s, 3H), 2.51 (s, 3H)], 2.83 (c, 2H), 4.69 (d, 1H),5.26 (d, 1H), 5.5 (b, 1H), 6.06 (vb, 1H), 6.6 (s, 1H), 7.15-7.39 (c,4H), 7.5 (c, 3H), 7.72-8.0 (c, 4H).

EXAMPLE 12N[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(naphth-2-10ylmethyl)urea

32% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.1 (c, 1H), 2.33-2.55 [total 10H, including2.37 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H)], 2.88 (c, 2H), 4.5 (d, 1H),4.8 (d, 1H), 5.6 (b, 1H), 6.08 (vb, 1H), 6.6 (s, 1H), 7.22 (c, 3H),7.47-7.54 (c, 4H), 7.83 (c, 3H), 7.93 (s, 1H).

EXAMPLE 13 N-[2,4-Bis(methylthio)-6methylpyridin-3-yl]-N'-(indan-1-yl)-N'-(4-t-butylbenzyl)urea

23% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.32 (s, 9H), 2.1 (c, 1H), 2.36-2.55 [total10H, including 2.38 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H)], 2.9 (c, 2H),4.29 (d, 1H), 4.6 (d, 1H), 5.52 (b, 1H), 6.05 (vb, 1H), 6.6 (s, 1H),7.22 (c, 4H), 7.32 (d, 2H), 7.39 (d, 2H).

EXAMPLE 14N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[indan-1-yl)-N'-(4-phenylbenzyl)urea

28% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.1 (c, 1H), 2.38-2.58 [total 10H, including2.39 (s, 3H), 2.47 (s, 3H), 2.5 (s, 3H)], 2.9 (c, 2H), 4.4 (d, 1H), 4.7(d, 1H), 5.54 (b, 1H), 6.02 (vb, 1H), 6.61 (s, 1H), 7.24 (c, 4H),7.31-7.52 (c, 51H), 7.6 (c, 4H).

EXAMPLE 15N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(naphth-1-ylmethyl)urea

20% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.4 (s, 3H), 2.48 (s, 3H), 2.53 (s, 3H), 3.07(dd, 2H), 3.33 (dd, 2H), 5.1 (s, 2H), 5.5 (m) and 5.57 (s) (total 2H),6.6 (s, 11H), 7.12 (c, 4H), 7.48-7.64 (c, 3H), 7.76-7.97 (c, 4H).

EXAMPLE 16N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(naphth-2-ylmethyl)urea

20% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.37 (s, 3H), 2.48 (s, 6H), 3.1 (dd, 2H), 3.34(dd, 2H)₁ 4.78 (s, 2H), 5.47 (p, 1H), 5.68 (s, 1H), 6.6 (s, 1H), 7.15(c, 4H), 7.38-7.58 (c, 3H), 7.87 (c, 3H), 7.95 (s, 1H).

EXAMPLE 17N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(naphth-2-ylmethyl)-N'-(2,4,6-trimethylbenzyl)urea

13% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.27 (s, 3H), 2.38 (s, 3H), 2.4 (s, 6H), 2.46(s, 3H), 2.5 (s, 3H), 3.07 (dd, 2H), 3.55 (dd, 2H), 4.16 (m, 1H), 4.77(s, 2H), 5.41 (s, 1H), 6.6 (s, 1H), 6.88 (s, 2H), 7.12 (c, 4H).

EXAMPLE 18

N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2,3-dichlorobenzyl)-N'-(indan-2-yl)urea

27% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.41 (s, 3H), 2.49 (s, 3H), 2.52 (s, 3H), 3.0(dd, 2H), 3.28 (dd, 2H), 4.68 (s, 2H), 5.32 (q, 1H), 5.54 (s, 1H), 6.63(s, 1H), 7.16 (c, 4H), 7.34 (t, 1H), 7.45 (d, 1H), 7.55 (d, 1H).

EXAMPLE 19N-[2,4-Bis(ethylthio)-6methythpyridin-3-yl]-N'-cycloheptyl-N'-(4-phenylbenzyl)urea

33% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.28, 1.32 (2t, 6H), 1.4-1.8 (C, 10H), 2.02(c, 2H), 2.42 (s, 3H), 2.86 (q, 2H), 3.09 (q, 2H), 4.37 (c, 1H), 4.62(s, 2H), 5.54 (s, 1H), 6.62 (s, 1H), 7.34 (t, 1H), 7.44 (t, 2H), 7.51(d, 2H), 7.6 (m, 4H).

EXAMPLE 20N-[2,4-Bis(ethylthio)-6methythpyridin-3-yl]-N'-cycloheptyl-N'-(fluoren-2-ylmethyl)urea

40% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.22, 1.24, 1.26, 1.27, 1.3 (2t, 6H), 1.4-1.8(c, 10H), 2.02 (c, 2H), 2.41 (s, 3H), 2.84 (q, 2H), 3.06 (q, 2H), 3.91(s, 2H), 4.42 (c, 1H), 4.65 (s, 2H), 5.55 (s, 1H), 6.6 (s,1H), 7.25-7.44(m, 3H), 7.54 (d, 1H), 7.68 (s, 1H), 7.78 (d, 2H),

EXAMPLE 21N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(naphth-2-ethyl)urea

31% yield

¹ H NMR (300 MHz, CDCl₃) δ1.2, 1.22, 1.25, 1.27, 1.3 (2t, 6H), 1.4-1.8(c, 1OH), 2.04 (c, 2H), 2.4 (s, 3H), 2.82 (q, 2H), 3.04 (q, 2H), 4.47(c, 1H), 4.73 (s, 2H), 5.6 (s, 1H), 6.59 (s, 1H), 7.48 (c, 3H), 7.85 (m,3H), 7.99 (s, 1H).

EXAMPLE 22N-[2.4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-[naphth-2-ylmethyl]urea

33% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.86 (t, 3H), 1.2-142 (c, 14H), 1.72 (c, 2H),2.43 (s, 3H), 2.88 (q, 2H), 3.11 (q, 2H), 3.44 (t, 2H), 4.79 (s, 2H),5.73 (s, 11H), 6.65 (s, 1H), 7.48 (m, 3H), 7.85 (m, 4H).

EXAMPLE 23N-[2,4-Bis(ethylthio)-methylpyridin-3-yl]-N'-heptyl-N'-(2,4,6-trimethylbenzyl)urea

34% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.86 (t, 3H), 1.23 (c, 8H), 1.3, 1.32, 1.33,1.35, 1.36, 1.38 (2t, 6H), 1.65 (c, 2H), 2.27 (s, 3H), 2.36 (s, 6H),2.46 (s, 3H), 2.91 (q, 2H), 3.05 (t, 2H), 3.15 (q, 2H), 4.71 (s, 2H),5.7 (s, 1H), 6.68 (s, 1H), 6.87 (s, 2H).

EXAMPLE 24N-[2,4-Bis(methylthio)-methylpyridin-3-yl]-N'-cycloheptyl-N'-(4-phenylbenzyl)urea

17% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.4-1.77 (c, 101H), 2.02 (c, 2H), 2.36 (s,3H), 2.45 (s, 3H), 2.46 (s, 3H), 4.38 (c, 1H), 4.62 (s, 2H), 5.51 (s,1H), 6.58 (s, 1H), 7.34 (t,1H), 7.4-7.54 (m, 4H), 7.61 (t, 4H).

EXAMPLE 25N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(fluoren-2-ylmethyl)urea

9% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.4-1.8 (c, 1OH), 2.02 (c, 2H), 2.35 (s, 3H),2.43 (s, 3H), 2.44 (s, 3H), 3.91 (s, 2H), 4.42 (c, 1H), 4.66 (s,1H),5.52 (s,1H), 6.57 (s, 1H), 7.24-7.45 (m, 3H), 7.55 (d, 11H), 7.67 (s,11H), 7.79 (d, 2H).

EXAMPLE 26N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(4-isopropylbenzyl)-N'-(1,2,3,4-tetrahydronaphth-2-yl)urea

13% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.25, 1.26, 1.27, 1.29, 1.31, 1.34, 1.36 (2tand d, 12H), 1.88 (m, 1H), 2.13 (c, 1H), 2.42 (s, 3H), 2.8-3.02 (m andq, 6H), 3.02-3.18 (c and q, 3H), 4.61 (s, 2H), 4.78 (c, 1H), 5.62 (s,1H), 6.63 (s, 1H), 7.08 (s, 4H), 7.26 (d, 2H), 7.4 (d, 2H).

EXAMPLE 27N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-heptyl-N'-(3-methylbenzo[b]thiophen-2-ylmethyl)urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.87 (t, 3H), 1.29-1.9 [c including 2t (1.26,1.28, 1.29, 1.31,1.32), total 14H], 1.75 (c, 2H), 2.42 (s, 3H), 2.45 (s,3H), 2.88 (q, 2H), 3.11 (q, 2H), 3.36 (t, 2H), 4.86 (s, 2H), 5.77 (s,1H), 6.67 (s, 1H), 7.28-7.4 (m, 2H), 7.66 (d, 1H), 7.79 (d, 1H).

EXAMPLE 28N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl-N'-(1,2,3,4-tetrahydronaphth-2-yl)-N'-(2,4,6-trimethylbenzyl)urea

26% yield

¹ H NMR (300 MHz, CDCl₃) δ1.32, 1.36 (2t, 6H), 2.06 (c, 1H), 2.15-2.35[c and s (2.25), total 4H], 2.42 (s, 6H), 2.44 (s, 3H), 2.6-2.96 (c,5H), 3.14 (q, 2H), 3.42 (m, 1H), 3.73 (c, 1H), 4.74 (s, 2H), 5.75 (s,1H), 6.66 (s, 1H), 6.84 (s, 2H), 7.06 (c, 4H).

EXAMPLE 29N-[2,4-Bis(methylthio-6-methylpyridin-3-yl]-N'-cycloheptyl-N'-(naphth-2-vimethyl)urea

18% yield

¹ H NMR (300 MHz, CDCl₃) δ1.49-1.74 (c, 10H), 2.04 (c, 2H), 2.33 (s,3H), 2.43 (s, 6H), 4.45 (c, 1H), 4.74 (s, 2H), 5.57 (s, 1H), 6.56 (s,1H), 7.48 (c, 3H), 7.85 (c, 3H), 7.97 (s, 1H).

EXAMPLE 30N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(4-isopropylbenzyl)urea

17% yield

¹ H NMR (300 MHz, CDCl₃) δ1.26 (d) and 1.29, 1.34 (2t) (total 12H), 2.42(s, 3H), 2.82-2.98 (m, 3H), 3.0-3.14 (m, 4H), 3.31 (dd, 2H), 4.57 (s,2H), 5.41 (p, 1H), 5.58 (s, 1H), 6.63 (s, 1H), 7.15 (c, 4H), 7.25 (d,2H), 7.33 (d, 2H).

EXAMPLE 31N-[2,4-Bis(ethylthio-6-methylpyridin-3-yl]-N'-(2.4-dimethylbenzyl)-N'-(indan-2-yl)urea

43% yield

¹ H NMR (300 MHz, CDCl₃ δ1.31, 1.35 (2t, 6H), 2.18 (s, 3H), 2.33 (s,3H), 2.43 (s, 3H), 2.89 (q, 2H), 3.0 (dd, 2H), 3.11 (q, 2H), 3.29 (dd,2H), 4.49 (s, 2H), 5.44 (p, 1H), 5.52 (s, 1H), 6.63 (s, 1H), 6.99 (s,1H), 7.1-7.2 (c, 5H), 7.49 (d, 1H).

EXAMPLE 32N-[2,4-Bis(methylthio)-6methylpyridin-3-yl]-N'-(4-isopropylbenzyl)-N'-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)urea

39% yield

¹ H NMR (300 MHz, CDCl₃) δ1.24 (d, 6H), 1.45-1.6 (m, 2H), 2.22 (c, 2H),2.36 (s, 3H), 2.46 (s, 3H), 2.7-2.96 (m, 6H), 4.45 (s, 2H), 4.72 (c,1H), 5.52 (s, 1H), 6.59 (s, 1H), 7.1 (m, 4H), 7.23 (d, 2H), 7.31 (d,2H).

EXAMPLE 33N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-(indan-2-yl)-N'-(2,4,6-trimethylbenzyl)urea

27% yield

¹ H NMR (300 MHz, CDCl₃ δ1.3, 1.34 (2t, 6H), 2.27 (s, 3H), 2.4 (s, 6H),2.41 (s, 3H), 2.88 (q, 2H), 2.98-3.18 (m, 4H), 3.57 (dd, 2H), 4.16 (p,1H), 4.77 (s, 2H), 5.43 (s, 1H), 6.62 (s, 1H), 6.87 (s, 2H), 7.11 (c,4H).

EXAMPLE 34N-[2,4-Bis(methylthio)-6methylpyridin-3-yl]-N'-[2-2-diphenylethyl]urea

A solution of 2,2-diphenylethylamine (148 mg, 0.75 mmol) and2,4-bis(methylthio)-6-methylpyridin-3yl isocyanate (170 mg, 0.75 mmol)in 15 ml dichloromethane was refluxed under nitrogen overnight. Thereaction mixture was then cooled to room temperature and concentrated invacuo. The residual solid was purified by column chromatography onsilica gel (200 g), eluting with 8:2 dichloromethane/ethyl acetate toyield the title compound as white solid (111 mg, 35% yield).

¹ H NMR (300 MHz, CDCl3) δ2.29 (s, 3H), 2.46 (s, 3H), 2.50 (s, 3H), 3.82(q, 2H), 4.18 (t, 1H), 6.53 (s, 1H), 7.12-7.28 (c, 12H).

The (2,2-diphenylethyl)urea derivatives of Examples 35-37 were preparedaccording to the method of Example 34.

EXAMPLE 35 N-(2,2-Diphenylethyl)-N'-(6-methylthioquinolin-5-yl)urea

63% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.27 (s, 3H), 3.62 (bd, 2H), 3.98 (t, 1H),6.39 (b, 1H), 6.88-7.08 (c, 10H), 7.54 (q, 1H), 7.62 (d, 1H), 7.95 (s,1H), 8.27 (d, 1H), 8.39 (d, 1H), 8.64 (m, 1H).

EXAMPLE 36N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-(2,2-diphenylethyl)urea

80% yield.

¹ H NMR (CDCl₃) δ2.42 (s, 6H), 2.60 (s, 3H), 3.82 (bm, 2H), 4.19 (t,1H), 4.50 (b, 1H), 5.07 (b, 1H), 7.09-7.27 (c, 10H).

EXAMPLE 37N-[4,6-Bis(methylthio)pyrimidin-5-yl]-N'-(2.2-diphenylethyl)urea

49% yield.

¹ H NMR (300 MHz, CDCl₃) δ2.43 (s, 3H), 3.84 (q, 2H), 4.20 (t,1H), 4.43(c, 1H), 5.46 (s, 1H), 7.12-7.31 (c, 10H), 8.59 (s, 1H).

EXAMPLE 38 N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-1(-phenylcyclopentyl)methyl]urea

A solution of (1-phenylcyclopentyl)methylamine (140 mg, 0.8 mmol) and2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (180 mg, 0.8 mmol)in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight.The reaction mixture was cooled to room temperature and diluted with 70ml ethyl acetate. The resulting solution was washed with 3×60 ml waterand 60 ml brine, dried (sodium sulfate), filtered and concentrated invacuo. The residue was chromatographed on silica gel (200 g), elutingwith 1:1 ethyl acetate/hexane to yield the title compound as a whitesolid (90 mg, 28% yield).

¹ H NMR (300 MHz, CDCl₃) δ1.6-1.9 (c, 6H), 2.03 (c, 2H), 2.35 (s, 3H),2.49 (s, 3H), 2.51 (s, 3H), 3.27 (d, 2H), 4.07 (b, 1H), 5.38 (b, 1H),6.55 (s, 1H), 7.12 (c, 5H).

The urea derivatives of Examples 39-46 were prepared according to themethod of Example 38.

EXAMPLE 39N-(6-Methylthioquinolin-5-yl)-N'-[(1-phenylcyclopentyl)methyl]urea

31% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.59-1.96 (c, 8H), 2.50 (s, 3H), 3.25 (d, 2H),3.91 (b, 1H), 5.96 (bs, 1H), 6.81 (c, 2H), 6.95 (c, 3H), 7.41 (q, 1H),7.57 (d, 1H), 8.05 (d, 1H), 8.22 (d, 1H), 8.86 (m, 1H).

EXAMPLE 40N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclopentyl}methyl]urea

24% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.6-1.9 (c, 6H), 2.0 (c, 2H), 2.27 (s, 3H),2.35 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 3.24 (d, 2H), 4.06 (b,1H),5.36 (b, ₁ H), 6.51 (s, 1H), 6.98 (q, 4H).

EXAMPLE 41N-[{1-(4-Methylphenyl)cyclopentyl}methyl-N'-(6-methylthioquinolin-5-yl]urea

28% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.6-1.98 (c, 8H), 2.19 (s, 3H), 2.52 (s, 3H),3.25 (d, 2H), 3.98 (b, 1H), 5.95 (b, 1H), 6.74 (q, 4H), 7.43 (q, 1H),7.60 (d, 1H), 8.11 (d, 1H), 8.24 (d, 1H), 8.87 (m, 1H).

EXAMPLE 42N-(6-Methylthioquinolin-5-yl)-N'-[(1-phenylcyclohexyl)methyl]urea

37% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.18-1.62 (c, 8H), 1.96 (c, 2H), 2.51 (s, 3H),3.25 (d, 2H), 3.86 (b, 1H), 5.99 (b, 1H), 6.97 (c, 5H), 7.43 (q, ₁ H),7.58 (d, 1H), 8.09 (d, 1H), 8.23 (d, 1H), 8.85 (m, ₁ H).

EXAMPLE 43N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(1-phenylcyclohexyl)methyl]urea

42% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.22-1.72 (c, 8H), 2.08 (c, 2H), 2.35 (s, 3H),2.50 (s, 3H), 2.51 (s, 3H), 3.25 (d, 2H), 3.95 (b, 1H), 5.38 (b, 1H),6.51 (s, 1H), 7.05-7.25 (c, 5H).

EXAMPLE 44N-[{1-(4-Methylphenyl)cyclohexyl}methyl]-N'-(6-methylthioquinolin-5-yl)urea

42% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.15-1.6 (c, 8H), 1.93 (c, 2H), 2.18 (s, 3H),2.15 (s, 3H), 3.22 (d, 2H), 3.81 (b, 1H), 5.94 (b, 1H), 6.77 (b, 4H),7.41 (q, 1H), 7.59 (d, 1H), 8.07 (d, 1H), 8.21 (d, 1H), 8.86 (m, 1H).

EXAMPLE 45N-[4,6-Bis(methylthio)-2-methylpyrimidin-5-yl]-N'-[{1-(4-methylphenyl)cyclohexyl}methyl]urea

42% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.23-1.68 (c, 8H), 2.06 (c, 2H), 2.30 (s, 3H),2.47 (s, 6H), 2.62 (s, 3H), 3.23 (d, 2H), 3.89 (b, 1H), 5.27 (b, 1H),7.04 (q, 4H).

EXAMPLE 46N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclohexyl}methyl]urea

24% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.2-1.7 (c, 8H), 2.06 (c, 2H), 2.28 (s, 3H),2.35 (s, 3H), 2.50 (s, 3H), 2.52 (s, 3H), 3.22 (d, 2H), 3.95 (b,1H),5.38 (b, 1H), 6.56 (s, 1H), 7.03 (q, 4H).

EXAMPLE 47N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea

A solution of 2-ethyl-2-phenylbutylamine (106 mg, 0.6 mmol) and2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (136 mg, 0.6 mmol)in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight.The reaction mixture was cooled to room temperature and diluted with 50ml ethyl acetate. The resulting solution was washed sequentially with3×25 ml water and 25 ml brine, dried (sodium sulfate), filtered andconcentrated in vacuo. The residue was chromatographed on silica gel(125 g), eluting with 65:35 hexane/ethyl acetate to yield the titlecompound as a white solid (67 mg, 28% yield).

¹ H NMR (300 MHz, CDCl₃) δ0.74 (t, 6H), 1.57-1.8 (c, 4H), 2.33 (s, 3H),2.47 (s, 3H), 2.48 (s, 3H), 3.41 (d, 2H), 3.95 (b, 1H), 5.36 (b, 1H),6.52 (s, 1H), 7.05-7.27 (c, 5H).

The urea derivatives of Examples 48-55 were prepared according to themethod of Example 47.

EXAMPLE 48N-[2,4-Bis(isoproylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.72 (t, 6H), 1.29 (d, 6H), 1.33 (d, 6H),1.57-1.8 (c, 4H), 2.45 (s, 3H), 3.39 (d and m, 3H), 3.93 (m and b, 2H),5.28 (b, 1H), 6.58 (s, 1H), 7.04-7.2 (c, 5H).

EXAMPLE 49 N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-{2-methylphenyl})butyl]urea

33% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.74 (t, 6H), 1.67 (m, 4H1), 2.28 (s, 3H),2.33 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 3.4 (d, 2H), 3.97 (b, 1H),5.35 (b, 1H), 6.53 (s, 1H), 6.94 (t, 1H), 6.98 (s, 2H), 7.08 (t, 1H).

EXAMPLE 50N-[2,4-Bis(methylthiol-6-methylpyridin-3-yl]-N'-[(2-phenyl-2-propyl)pentyl]urea

88% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.85 (t, 6H), 0.88-1.3 (c, 4H), 1.59 (c, 4H),2.32 (s, 3H), 2.47 (s, 3H), 2.49 (s, 3H), 3.4 (d, 2H), 3.96 (b, 1H),5.33 (b, 1H), 6.52 (s, 1H), 7.05-7.24 (c, 5H).

EXAMPLE 51N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2-methylphenyl}-2-propyl)pentyl]urea

43% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.84 (t, 6H), 0.961.3 (c, 4H), 1.58 (c, 4H),2.27 (s, 3H), 2.32 (s, 3H), 2.46 (s, 3H), 2.47 (s, 3H), 3.39 (d, 2H),3.96 (b, 1H), 5.3 (s, 1H), 6.52 (s, 1H), 6.93 (t, 1H), 6.97 (s, 2H),7.06 (t, 1H).

EXAMPLE 52N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2-methylphenyl}-2-butyl)hexyl]urea

57% yield.

¹ H NMR (300 MHz, CDCl3) δ0.84 (t, 6H), 0.94-1.33 (c, 8H), 1.59 (c, 4H),2.27 (s, 3H), 2.32 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H), 3.4 (d, 2H),3.96 (b, 1H), 5.29 (s, 1H), 6.53 (s, 1H), 6.93 (c, 3H), 7.07 (t, 1H).

EXAMPLE 53N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethoxyphenyl}-2-propyl)pentyl]urea

30% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 6H), 0.94-1.3 (c, 4H), 1.5-1.8 (c,4H), 2.33 (s, 3H), 2.45 (s, 3H), 2.48 (s, 3H), 3.6 (d, 2H), 3.68 (s,3H), 3.74 (s, 3H), 4.11 (b, 1h), 5.38 (b, 1H), 6.5 (s, 1H), 6.64 (s andm, total 3H).

EXAMPLE 54N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,3-dimethoxyphenyl}-2-propyl)pentyl]urea

45% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 6H), 0.98-1.25 (c, 4H), 1.67 (c, 4H),2.32 (s, 3H), 2.44 (s, 3H), 2.47 (s, 3H), 3.59 (d, 2H), 3.78 (s, 3H),3.82 (s, 3H), 4.08 (b, 1H), 5.33 (b, 1H), 6.51 (s, 1H), 6.66 (d, 1H),6.77 (d, 1H), 6.84 (t, 1H).

EXAMPLE 55N-2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethylphenyl-}2-propyl)pentyl]urea

30% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 6H), 1.08 (m, 4H), 1.65 (c, 4H), 2.22(s, 3H), 2.32 (s, 3H), 2.38 (s, 3H), 2.45 (s, 3H), 2.46 (s, 3H), 3.57(d, 2H), 4.04 (b, 1H), 5.37 (b, 1H), 6.49 (s, 1H), 6.85 (c, 3H).

EXAMPLE 56N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2-methylphenyl)hexyl]urea

A solution of 2-(2-methylphenyl)hexylamine (153 mg, 0.8 mmol) and2,4-bis(methylthio)-6-methylpyridin-3-yl isocyanate (180 mg, 0.8 mmol)in 3 ml dimethylformamide was heated at 80° C. under nitrogen overnight.The reaction mixture was cooled to room temperature and diluted with 60ml ethyl acetate. The resulting solution was washed sequentially with3×50 ml water and 50 ml brine, dried (sodium sulfate), filtered andconcentrated in vacuo. The residue was chromatographed on silica gel(200 g), eluting with 7:3 hexane/ethyl acetate to yield the titlecompound as a white solid (110 mg, 33% yield).

¹ H NMR (300 MHz, CDCl₃) δ0.80 (t, 3H), 1.06-1.32 (c, 4H), 1.46-1.74 (c,2H), 2.23 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 2.48 (s, 3H), 3.03-3.26(c, 2H), 3.51 (p, 1H), 4.21 (b, 1H), 5.33 (b, 1H), 6.52 (s, 1H),7.01-7.11 (c, 4H).

The urea derivatives of Examples 57-82 were prepared according to themethod of Example 56.

EXAMPLE 57 N- [2-(2-Methylphenyl)hexyl]-N'-[6-methylthioquinolin-5-yl]urea

28% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.80 (t, 3H) 0.98-1.28 (c, 4H), 1.4-1.65 (c,2H), 2.08 (s, 3H), 2.48 (s, 3H), 2.96-3.27 (c, 2H), 3.51 (p, 1H), 4.10(b, 1H), 5.94 (b, 1H), 6.87-7.02 (c, 4H), 7.36 (q, 1H), 7.57 (d, 1H),8.06 (d, 1H), 8.14 (d, 1H), 8.82 (m, 1H).

EXAMPLE 58N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(4-methylphenyl)heptyl]urea

24% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.80 (t, 3H), 1.07-1.28 (c, 6H), 1.45-1.7 (c,2H), 2.28 (s, 3H), 2.32 (s, 3H), 2.45 (s, 3H), 2.48 (s, 3H), 2.65 (c,1H), 3.10 (c, 1H), 3.56 (p, 1H), 4.21 (b, 1H), 5.35 (b, 1H), 6.54 (s,1H), 6.98 (q, 4H).

EXAMPLE 59N-[2-(4-Methylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

30% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.02-1.26 (c, 6H), 1.46-1.62 (c,2H), 2.23 (s, 3H), 2.48 (s, 3H), 2.57 (c, 1H), 3.10 (c, 1H), 3.56 (p,1H), 4.11 (b, 1H), 5.96 (s, 1H), 6.81 (q, 4H), 7.34 (q, 1H), 7.57 (d,1H), 8.04 (d, 1H), 8.13 (d, 1H), 8.82 (m, 1H).

EXAMPLE 60N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)heptyl]urea

26% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.06-1.32 (c, 6H), 1.45-1.72 (c,2H), 2.28 (s, 3H), 2.34 (s, 3H), 2.48 (s, 3H), 2.50 (s, 3H), 2.67 (c,1H), 3.14 (m, 1H), 3.57 (p, 1H), 4.31 (b, 1H), 5.47 (b, 1H), 6.56 (s,1H), 6.87 (d, 1H), 6.89 (s, 1H), 6,96 (d, 1H), 7.09 (t, 1H).

EXAMPLE 61N-[2-(3-Methylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

24% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.8 (t, 3H) 1.0-1.3 (c, 6H), 1.37-1.64 (c,2H), 2.19 (s, 3H), 2.48 (s, 3H), 2.59 (c, 1H), 3.14 (m, 1H), 3.57 (p,1H), 4.23 (b, 1H), 6.11 (b, 1H), 6.7 (d, 1H), 6.72 (s, 1H), 6.88 (d,1H), 6.97 (t, 1H), 7.35 (q, 1H), 7.56 (d, 1H), 8.04 (d, 1H), 8.14 (d,1H), 8.81 (m, 1H).

EXAMPLE 62 N-[2-(3-Methylphenyl)heptyl]-N'-(6-methoxyguinolin-5-yl)urea

53% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.8 (t, 3H), 1.04-1.28 (c, 6H), 1.38-1.63 (c,2H), 2.21 (s, 3H), 2.6 (m, 1H), 3.13 (m, 1H), 3.59 (m, 1H), 3.9 (s, 3H),4.22 (b, 1H), 5.98 (b, 1H), 6.71 (d, 1H), 6.73 (s, 1H), 6.91 (d, ₁ H),7.01 (t, 1H), 7.31 (q, 1H), 7.46 (d, 1H), 8.07 (d, 1H), 8.18 (d, 1H),8.77 (m, 1H).

EXAMPLE 63N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)hexyl]urea

32% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.04-1.32 (c, 4H), 1.45-1.74 (c,2H), 2.18 (s, 3H), 2.23 (s, 3H), 2.31 (s, 3H), 2.45 (s, 3H), 2.49 (s,3H), 3.04 (m, 1H), 3.2 (m, 1H), 3.53 (p, 1H), 4.2 (b, 1H), 5.34 (b, 1H),6.53 (s, 1H), 6.84 (d, 1H), 6.93 (d, 1H).

EXAMPLE 64N-[2-(2,5-Dimethylphenyl)hexyl]-N'-(6-methylthioquinolin-5-yl)urea

33% yield.

¹ H NMR (300 MHz, CDCl₃ +DMSO-d₆) δ0.76 (t, 3H), 1.0-1.26 (c, 4H),1.35-1.65 (c, 2H), 2.1 (s, 3H), 2.17 (s, 3H), 2.44 (s, 3H), 3.0 (c, 1H),3.15 (m, 1H), 3.56 (p, 1H), 4.96 (b, 1H), 6.74-6.92 [total 4H, including6.78 (d, 1H), 6.81 (s, 1H), 6.87 (d, 1H and b)], 7.34 (q, 1H), 7.56 (d,1H), 8.02 (d, 1H), 8.16 (d, 1H), 8.76 (m, 1H).

EXAMPLE 65N-[2-(2,5-Dimethylphenyl)hexyl]-N'-(6-methoxyguinolin-5-yl)urea

37% yield.

¹ H NMR (300 MHz, CDCl₃ +DMSO-d₆) δ0.76 (t, 3H), 1.0-1.28 (c, 4H),1.35-1.65 (c, 2H), 2.07 (s, 3H), 2.17 (s, 3H), 3.0 (c, 1H), 3.11 (m,1H), 3.57 (p, 1H), 3.86 (s, 3H), 4.71 (b, ₁ H), 6.46 (b, 1H), 6.77 (s,1H), 6.78 (d, 1H), 6.86 (d, 1H), 7.28 (q, 1H), 7.42 (d, 1H), 8.0 (d,1H), 8.16 (d, 1H), 8.71 (m, 1H).

EXAMPLE 66N-[2,4-Bis(methylthio)-6-methylpyridin-3yl-N'-[2-(2,5dimethylphenyl)heptyl]urea

28% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.08-1.3 (c, 6H), 1.43-1.74 (c,2H), 2.19 (s, 3H), 2.23 (s, 3H), 2.33 (s, 3H), 2.48 (s, 3H), 2.53 (s,3H), 3.04 (c, 1H), 3.21 (m, 1H), 3.51 (p, 1H), 4.35 (b, 1H), 5.0 (b,1H), 6.56 (s, 1H), 6.84 (d, 1H), 6.86 (d, 1H), 6.93 (d, 1H).

EXAMPLE 67N-[2,4-Bis(methylthio)-6methylpyridin-3-yl]-N'-[2-(2,4-dimethylphenyl)hexyl]urea

68% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.05-1.31 (c, 4H), 1.42-1.75 (c,2H), 2.2 (s, 3H), 2.26 (s, 3H), 2.32 (s, 3H), 2.46 (s, 3H), 2.52 (s,3H), 3.04 (c, 1H), 3.18 (m, 1H), 3.49 (p, 1H), 4.3 (b, 1H), 5.46 (b,1H), 6.55 (s, 1H), 6.86 (s, 1H), 6.89 (d, 1H), 6.95 (d, 1H).

EXAMPLE 68N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)hexyl]urea

60% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.05-1.33 (c, 4H), 1.45-1.75 (c,2H), 2.28 (s, 3H), 2.34 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 2.67 (m,1H), 3.15 (m, 1H), 3.57 (p, 1H), 4.34 (b, 1H), 5.48 (b, 1H), 6.57 (s,1H), 6.88 (d, 1H), 6.89 (s, 1H), 6.96 (d, 1H), 7.1 (t, 1H).

EXAMPLE 69N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,4-dimethylphenyl)heptyl]urea

59% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.08-1.28 (c, 6H), 1.42-1.72 (c,2H), 2.19 (s, 3H), 2.26 (s, 3H), 2.32 (s, 3H), 2.45 (s, 3H), 2.51 (s,3H), 3.04 (c, 1H), 3.18 (m, 1H), 3.49 (p, 1H), 4.24 (b, 1H), 5.38 (b,1H), 6.55 (s, 1H), 6.86 (s, 1H), 6.89 (d, 1H), 6.95 (d, 1H).

EXAMPLE 70N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)heptyl]urea

50% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.14-1.34 (c, 6H), 1.56-1.92 (c,2H), 2.14 (s, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 3.48 (m, 1H), 3.6 (p,1H), 3.73 (c, 1H), 4.26 (b, 1H), 5.37 (b, 1H), 6.39 (s, 1H), 7.28 (d,1H), 7.36 (t, 1H), 7.47 (c, 2H), 7.67 (d, 1H), 7.82 (c, 1H), 8.13 (c,1H).

EXAMPLE 71N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-2-yl)hexyl]urea

36% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.8 (t, 3H), 1.06-1.35 (c, 4H), 1.55-1.81 (c,2H), 2.07 (s, 3H), 2.37 (s, 3H), 2.4 (s, 3H), 2.9 (c, 1H), 3.24 (m, 1H),3.66 (p, 1H), 4.25 (b, 1H), 5.39 (b, 1H), 6.34 (s, 1H), 7.25 (m, 1H),7.4-7.51 (c, 3H), 7.68-7.87 (c, 3H).

EXAMPLE 72 N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)hexyl]urea

36% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.1-1.34 (c, 4H), 1.56-1.92 (c,2H), 2.13 (s, 3H), 2.37 (s, 3H), 2.44 (s, 3H), 3.47 (m, 1H), 3.6 (p,1H), 3.73 (c, 1H), 4.28 (b, 1H), 5.36 (b, 1H), 6.4 (s, 1H), 7.28 (d,1H), 7.35 (t, 1H), 7.46 (c, 2H), 7.66 (d, 1H), 7.82 (c, 1H), 8.12 (c,1H).

EXAMPLE 73 N-(6-Methylthioquinolin-5-yl)-N'-[2-(naphth-1-yl)hexyl]urea

34% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.78 (t, 3H), 1.1-1.3 (c, 4H), 1.56-1.82 (c,2H), 2.35 (s, 3H), 3.44 (c, 1H), 3.7 (c, 2H), 4.21 (b, 1H), 5.98 (s,1H), 7.08 (c, 2H), 7.22 (t, 1H), 7.42 (c, 3H), 7.6 (d, 1H), 7.8 (d, 1H),7.9 (d, 1H), 7.94 (d, 1H), 8.03 (d, 1H), 8.7 (m, 1H),

EXAMPLE 74N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,3-dimethoxyphenyl)heptyl]urea

29% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.1-1.3 (c, 6H), 1.45-1.77 (c,2H), 2.33 (s, 3H), 2.48 (s, 3H), 2.53 (s, 3H), 3.12-3.35 (c, 2H), 3.45(p, 1H), 3.69 (s, 3H), 3.84 (s, 3H), 4.54 (b, 1H), 5.52 (b, 1H), 6.59(s, 1H), 6.7 (d, 1H), 6.73 (d, 1H), 6.95 (t, 1H).

EXAMPLE 75N-[2-(2,3-Dimethoxaphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

31% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.05-1.3 (c, 6H), 1.42-1.65 (c,2H), 2.49 (s, 3H), 3.12 (c, 1H), 3.27 (c, 1H), 3.46 (m, 1H), 3.53 (s,3H), 3.8 (s, 3H), 4.44 (b, 1H), 6.04 (b, 1H), 6.56 (d, 1H), 6.66 (d,1H), 6.85 (t, 1H), 7.37 (q, 1H), 7.61 (d, 1H), 8.08 (d, 1H), 8.17 (d,1H), 8.82 (m, 1H).

EXAMPLE 76N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)octyl]urea

47% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.19 (b, 8H), 1.46-1.72 (c, 2H),2.27 (s, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H), 2.66 (c, 1H),3.13 (c, 1H), 3.58 (p, 1H), 4.23 (b, 1H), 5.35 (s, 1H), 6.55 (s, 1H),6.87 (d) and 6.88 (s) (total 2H), 6.96 (d, 1H), 7.09 (t, 1H).

EXAMPLE 77 N-[2-(3-Methylphenyl)octyl]-N'-(6-methoxyguinolin-5-yl)urea

54% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.18 (b, 8H), 1.53 (c, 2H), 2.22(s, 3H), 2.61 (m, 1H), 3.14 (m, 1H), 3.6 (p, 1H), 3.91 (s, 3H), 4.24 (b,1H), 5.99 (s, 1H), 6.72 (d) and 6.73 (s) (total 2H), 6.92 (d, 1H), 7.01(t, 1H), 7.33 (q, 1H), 7.47 (d, 1H), 8.09 (d, 1H), 8.19 (d, 1H), 8.77(q, 1H).

EXAMPLE 78N-[2-(3-Methylphenyl)octyl]-N'-(6-methylthioquinolin-5-yl)urea

25% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.17 (b, 8H), 1.52 (c, 2H), 2.2(s, 3H), 2.49 (s, 3H), 2.6 (m, 1H), 3.15 (m, 1H), 3.58 (p, 1H), 4.21 (b,1H), 6.05 (s, 1H), 6.71 (d) and 6.73 (s) (total 2H), 6.89 (d, 1H), 6.99(t, 1H), 7.37 (q,1H), 7.58 (d, 1H), 8.07 (d, 1H) 8.17 (d, 1H), 8.82 (t,1H).

EXAMPLE 79 N-[2-(naphth-1-yl)heptyl]-N'-(6-methoxyguinolin-5-yl)urea

58% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.19 (b, 6H), 1.7 (b, 2H), 3.41(c, 1H), 3.72 (c) and 3.75 (s) (total 5H), 4.21 (b, 1H), 5.88 (s, 1H),7.02 (q, 1H), 7.13 (d, 1H) 7.25 (t, 1H), 7.33 (d, 1H), 7.45 (m, 2H),7.63 (d, 1H), 7.83 (d, 1H), 7.92 (d, 1H), 7.98 (d, 1H), 8.04 (d, 1H),8.65 (m, 1H).

EXAMPLE 80 N-[2-(naphth-1-yl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

47% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.17 (b, 6H), 1.7 (b, 2H), 2.35(s, 3H), 3.44 (c, 1H), 3.6-3.78 (c, 2H), 4.22 (b, 1H), 5.97 (s, 1H),7.06 (q, 1H), 7.12 (d, 1H), 7.23 (t, 1H), 7.43 (m, 3H), 7.6 (d, 1H),7.81 (d, 1H), 7.9 (d, 1H), 7.96 (d, 1H), 8.03 (d, 1H), 8.69 (m, 1H).

EXAMPLE 81N-[2-(2,4-Dimethylphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

41% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.14 (b, 6H), 1.48 (c, 2H), 2.0(s, 3H), 2.2 (s, 3H), 2.47 (s, 3H), 2.95 (c, 1H), 3.15 (m, 1H), 3.5 (p,1H), 4.06 (b, 1H), 5.91 (s, 1H), 6.71 (s, 1H), 6.75 (s, 2H), 7.32 (q,1H), 7.55 (d, 1H), 8.03 (d, 1H), 8.03 (d, 1H), 8.11 (d, 1H), 8.82 (q,1H).

EXAMPLE 82N-[2-(2,4-Dimethylphenyl)heptyl]-N'-(6-methoxyquinolin-5-yl)urea

57% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.8 (t, 3H), 1.16 (b, 6H), 1.49 (c, 2H), 2.02(s, 3H), 2.23 (s, 3H), 2.97 (c, 1H), 3.13 (m, 1H), 3.55 (p, 1H), 3.9 (s,3H), 4.14 (b, 1H), 5.89 (s, 1H), 6.75 (s, 1H), 6.78 (s, 2H), 7.28 (q,1H), 7.44 (d, 1H), 8.04 (d, 1H), 8.14 (d, 1H), 8.77 (q, 1H).

EXAMPLE 83N-[2,4-Bis(methyl)-6-methylpyridin-3-yl]-N'-[2-(3,4,5-trimethoxyphenyl)heptyl]urea

45% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.23 (b, 6H), 1.4-1.7 (c, 2H),2.3 (s, 3H), 2.45 (s, 3H), 2.48 (s, 3H), 2.64 (c, 1H), 3.12 (m, 1H),3.57 (q, 1H), 3.79 (s, 6H), 3.82 (s, 3H), 4.23 (b, 1H), 5.39 (b, 1H),6.27 (s, 2H), 6.54 (s, 1H).

EXAMPLE 84N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethyl-4-methoxyphenyl)heptyl]urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.19 (b, 6H), 1.5 (c, 1H), 1.63(c, 1H), 2.11 (s, 3H), 2.2 (s, 3H), 2.34 (s, 3H), 2.49 (s, 3H), 2.54 (s,3H), 2.98 (c, 1H), 3.18 (m, 1H), 3.49 (p, 1H), 3.79 (s, 3H), 4.2 (b,1H), 5.35 (b, 1H), 6.5 (s, 1H), 6.58 (s, 1H), 6.79 (s, 1H).

EXAMPLE 85N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethoxyphenyl)heptyl]urea

40% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.2 (b, 6H), 1.63 (b, 2H), 2.34(s, 3H), 2.46 (s, 3H), 2.51 (s, 3H), 3.15 (c, 1H), 3.26-3.5 (c, 2H),3.62 (s, 3H), 3.73 (s, 3H), 4.48 (b, 1H), 5.54 (b, 1H), 6.58 (s, 1H),6.61-6.71 (c, 3H).

EXAMPLE 86N-2-(2,5-Dimethoxyphenyl)heptyl]-N'-(6-methylthioquinolin-5-yl)urea

30% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.17 (b, 6H), 1.54 (b, 2H), 2.49(s, 3H), 3.08 (c, 1H), 3.24-3.4 (m including s at 3.38, total 4H), 3.45(p, 1H), 3.72 (s, 3H), 4.42 (b, 1H), 6.05 (b, 1H), 6.49 (d, 1H),6.52-6.61 (c, 2H), 7.35 (q, 1H), 7.61 (d, 1H), 8.09 (d, 1H), 8.14 (d,1H), 8.81 (m, 1H).

EXAMPLE 87N-[2-(2,5-Dimethoxyphenyl)heptyl-N'-(6-methoxyquinolin-5-yl)urea

39% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 1.18 (b, 6H), 1.55 (b, 2H), 3.09(c, 1H), 3.27 (m, 1H), 3.37 (s, 3H), 3.49 (p, 1H), 3.72 (s, 3H), 3.9 (s,3H), 4.45 (b, 1H), 5.98 (b, 1H), 6.51 (d, 1H), 6.55-6.63 (c, 2H), 7.31(q, 1H), 7.48 (d, 1H), 8.09 (d, 1H), 8.17 (d, 1H), 8.77 (q, 1H).

EXAMPLE 88N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethoxyphenyl)heptyl]urea

45% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.2 (b, 6H), 1.44-1.68 (c, 2H),2.33 (s, 3H), 2.44 (s, 3H), 2.47 (s, 3H), 2.65 (c, 1H), 3.11 (m, 1H),3.58 (p, 1H), 3.74 (s, 6H), 4.22 (b, 1H), 5.34 (s, 1H), 6.24 (s and c,3H), 6.54 (s, 1H).

EXAMPLE 89N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethoxyphenyl)octyl]urea

50% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.2 (b, 8H), 1.64 (b, 2H), 2.33(s, 3H), 2.45 (s, 3H), 2.5 (s, 3H), 3.15 (c, 1H), 3.27-3.5 (c, 2H), 3.61(s, 3H), 3.73 (s, 3H), 4.43 (b, 1H), 5.47 (b, 1H), 6.57 (s, 1H),6.6-6.71 (c, 3H).

EXAMPLE 90N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-2-[2-(3-methylphenyl)-6,6,6-trifluorohexyl]urea

34% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.42 (c, 2H), 1.55-1.82 (c, 2H), 2.0 (c, 2H),2.28 (s, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.48 (s, 3H), 2.68 (c, 1H),3.17 (m, 1H), 3.56 (p, 1H), 4.28 (b, 1H), 5.39 (s, 1H), 6.56 (s, 1H),6.88 (d) and 6.89 (s) (total 2H), 6.98 (d, 1H), 7.12 (t, 1H).

EXAMPLE 91N-[2-(3-Methylphenyl)heptyl]-N'-(6-pentylthioquinolin-5-yl)urea

53% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.81 (t, 3H), 0.9 (t, 3H), 1.04-1.7 (c, 14H),2.2 (s, 3H), 2.59 (c, 1H), 2.93 (t, 2H), 3.14 (m, 1H), 3.59 (p, 1H),4.15 (b, 1H), 6.11 (s, 1H), 6.69 (d) and 6.71 (s) (total 2H), 6.89 (d,1H), 6.99 (t, 1H), 7.33 (q, 1H), 7.62 (d, 1H), 7.98 (d, 1H), 8.13 (d,1H), 8.82 (q, 1H).

EXAMPLE 92N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-{2,-(5chlorobenzo[b]thiophen-3-yl)heptyl}urea

36% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.22 (b, 6H), 1.63 (b, 2H), 2.23(s, 3H), 2.4 (s, 3H), 2.46 (s, 3H), 3.21 (m, 1H), 3.51 (c, 2H), 4.32 (b,1H), 5.44 (b, 1H), 6.48 (s, 1H), 7.13 (s, 1H), 7.29 (c, 1H), 7.72 (d,1H), 7.41 (s, 1H).

EXAMPLE 93N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5dimethylphenyl)heptyl]urea

34% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.21 (b, 6H), 1.57 (b, 2H), 2.23(s, 6H), 2.33 (s, 3H), 2.46 (s, 3H), 2.48 (s, 3H), 2.61 (c, 1H), 3.13(m, 1H), 3.56 (p, 1H), 4.21 (b, 1H), 5.33 (s, 1H), 6.55 (s, 1H), 6.67(s, 2H), 6.78 (s, 1H).

EXAMPLE 94N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)octyl]urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.84 (t, 3H), 1.19 (b, 8H), 1.6 (b, 2H), 2.18(s, 3H), 2.23 (s, 3H), 2.31 (s, 3H), 2,45 (s, 3H), 2,49 (s, 3H), 3.04(c, 1H), 3.2 (m, 1H), 3.52 (p, 1H), 4.22 (b, 1H), 5.37 (b, 1H), 6.54 (s,1H), 6.84 (d) and 6.85 (s), (total 2H), 6.92 (d, 1H).

EXAMPLE 95N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[5-methyl-2-{3-methylphenyl}hexyl]urea

44% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79, 0.8, 0.81, 0.82 (2d, 6H), 0.92-1.18 (c,2H), 1.38-1.74 (c, 3H), 2.28 (s, 3H), 2.33 (s, 3H), 2.46 (s, 3H), 2.48(s, 3H), 2.63 (c, 1H), 3.14 (m, 1H), 3.58 (p, 1H), 4.22 (b, 1H), 5.36(s, 1H), 6.55 (s, 1H), 6.87 (d) and 6.68 (s) (total 2H), 6.96 (d, 1H),7.09 (t, 1H).

EXAMPLE 96N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-{2,5-dimethylphenyl}-4-phenylbutyl]urea

33% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.8-1.96 (m, 1H), 1.99-2.14 (m) and 2.11 (s)(total 4H), 2.24 (s, 3H), 2.3 (s, 3H), 2.4-2.54 (m, 8H) including 2.44(s, 3H) and 2.49 (s, 3H), 3.08 (c, 1H), 3.3 (m, 1H), 3.49 (p, 1H), 4.25(b, 1H), 5.37 (s, 1H), 6.54 (s, 1H), 6.87 (d) and (6.9 (s) (total 2H),6.95 (d, 1H), 7.08 (d) and 7.09 (s) (total 2H), 7.14 (m, 1H), 7.23 (m,2H).

EXAMPLE 97N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-5-phenylpentyl]urea

19% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.4-1.8 (c, 4H), 2.17 (s, 3H), 2.22 (s, 3H),2.3 (s, 3H), 2.43 (s, 3H), 2.48 (s, 3H), 2.53 (c, 2H), 3.08 (c, 1H), 3.2(m, 1H), 3.52 (p, 1H), 4.22 (b, 1H), 5.36 (s, 1H), 6.52 (s, 1H), 6.81(s) and 6.83 (d) (total 2H), 6.91 (d, 1H), 7.08 (d, 2H), 7.13 (m, 1H),7.23 (m, 2H).

EXAMPLE 98N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-N'-[2-(naphth-1-yl)-6-methylheptyl]urea

59% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.76 (t, 6H), 1.06-1.34 (c, m, 4H), 1.43 (h,1H), 1.75 (c, 2H), 2.13 (s, 3H), 2.37 (s, 3H), 2.43 (s, 3H), 3.48 (m,1H), 3.56-3.82 (c, 2H), 4.21 (c, 1H), 5.28 (s, 1H), 6.37 (s, 1H), 7.28(m, 1H), 7.36 (t, 1H), 7.46 (m, 2H), 7.67 (d, 1H), 7.83 (m, 1H), 8.13(m, 1H).

EXAMPLE 99N-[2,4-Bis(ethylthio)-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)-6-methylheptyl]urea

31% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.74, 0.76, 0.79 (2d, 6H), 1.06-1.32 (m, c,10H), 1.42 (h, 1H), 1.78 (c, 2H), 2.42 (s, 3H), 2.68 (q, 2H), 3.02 (q,2H), 3.53 (m, 2H), 3.72 (c, 1H), 4.20 (c, 1H), 5.27 (s, 1H), 6.42 (s,1H), 7.28 (m, 1H), 7.34 (t, 1H), 7.46 (m, 2H), 7.67 (d, 1H), 7.81 (m,1H), 8.12 (m, 1H).

EXAMPLE 100N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-methylheptyl]urea

38% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.77, 0.79, 0.81 (2d, 6H), 1.04-1.72 [c, mincluding 2t (1.29, 1.31, 6H), total 13H], 2.18 (s, 3H), 2.22 (s, 3H),2.46 (s, 3H), 2.81 (q, 2H), 2.98-3.25 [m including q (3.08, 2H), total4H], 3.53 (p, 1H), 4.2 (c, 1H), 5.32 (s, 1H), 5.56 (s, 1H), 6.84 (d,1H), 6.92 (d, 1H), 7.26 (s, 1H).

EXAMPLE 101N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(naphth-1-yl)heptyl]urea

15% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.23 (m, c, 12H), 1.65-1.94 (c,2H), 2.42 (s, 3H), 2.68 (q, 2H), 3.02 (q, 2H), 3.54 (c, 2H), 3.72 (c,1H), 4.22 (c, 1H), 5.28 (s, 1H), 6.42 (s, 1H), 7.32 (m, 2H), 7.45 (m,2H), 7.67 (d, 1H), 7.82 (m, 1H), 8.11 (m, 1H).

EXAMPLE 102N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6-phenylhexyl]urea

57% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.14-1.36 [c including 2t (1.28, 1.3, 6H),total 10H], 1.48-1.8 (m, c, 4H), 2.17 (s, 3H), 2.23 (s, 3H), 2.46 (s,3H), 2.52 (t, 2H), 2.81 (q, 2H), 2.29-3.13 [c and q (3.07, 2H) total3H], 3.2 (m, 1H), 3.52 (p, 1H), 4.21 (c, 1H), 5.33 (s, 1H), 6.56 (s,1H), 6.85 (d, 1H), 6.93 (d, 1H), 7.13 (m, 3H), 7.24 (m, 3H).

EXAMPLE 103N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)heptyl]urea

48% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.2 (c, 6H), 1.29, 1.31 (2t,6H), 1.47 -1.72 (c, 2H), 2.17 (s, 3H), 2.23 (s, 3H), 2.46 (s, 3H), 2.82(q, 2H), 2.98-3.13 [c including q (3.08), total 3H], 3.19 (m, 1H), 3.53(p, 1H), 4.18 (b, 1H), 5.29 (s, 1H), 6.56 (s, 1H), 6.84 (d) and 6.85(s), total 2H, 6.92 (d, 1H).

EXAMPLE 104N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,4,6-trimethylphenyl)octyl]urea

27% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.2 (c, 8H), 1.7 (c, 2H), 2.16(s, 3H), 2.22 (s, 3H), 2.28 (s, 3H), 2.3 (s, 3H), 2.42 (s, 3H), 2.48 (s,3H), 3.28 (c, 2H), 3.68 (m, 1H), 4.14 (b, 1H), 5.29 (s, 1H), 6.48 (s,1H), 6.66 (s, 1H), 6.69 (s, 1H).

EXAMPLE 105N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-6,6,6-trifluorohexyl]urea

20% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.29,1.32 (2t, 6H), 1.43 (c, 2H), 1.63 (c,1H), 1.78 (c, 1H), 2.0 (c, 2H), 2.2 (s, 3H), 2.24 (s, 3H), 2.46 (s, 3H),2.84 (q, 2H), 3.0-3.15 [c including t (3.09) total 3H], 3.22 (m, 1H),3.49 (p, 1H), 4.25 (b, 1H), 5.34 (s, 1H), 6.58 (s, 1H), 6.86 (d, 2H),6.95 (d, 1H).

EXAMPLE 106N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea

10% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (c, 3H), 1.24 (c, 6H), 1.74 (c, 2H), 2.2(s, 3H), 2.4 (s, 3H), 2.46 (s, 6H), 3.25 (m, 1H), 3.5 (t, 2H), 4.28 (b,1H), 5.37 (s, 1H), 6.45 (s, 1H), 6.99 (s, 1H), 7.15 (d, 1H), 7.55 (s,1H), 7.71 (d, 1H).

EXAMPLE 107N-[2,4-Bis(methylthio-6-methylpyridin-3-yl]-N'-[2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]urea

32% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (c, 3H), 1.2 (c, 6H), 1.79 (c, 1H), 1.91(c, 1H), 2.23 (s, 3H), 2.37 (s, 3H), 2.46 (s, 3H), 3.4-3.59 (c, 2H),3.79 (c, 1H), 4.27 (b, 1H), 5.36 (s, 1H), 6.47 (s, 1H), 7.3 (m, 2H),7.67 (m, 1H), 7.76 (c, 1H).

EXAMPLE 108N-[2-(2,5-Dimethylphenyl)heptyl]-N'-[6-methylthioquinolin-5-yl]urea

33% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.16 (c, 6H), 1.5 (c, 2H), 2.0(s, 3H), 2.13 (s, 3H), 2.47 (s, 3H), 2.96 (m, 1H), 3.16 (m, 1H), 3.55(p, 1H), 4.09 (b, 1H), 5.97 (s, 1H), 6.7 (s, 1H), 6.77 (q, 2H), 7.34 (q,1H), 7.56 (d, 1H), 8.03 (d, 1H), 8.2 (d, 1H), 8.82 (q, 1H).

EXAMPLE 109N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N-[2-(2,5-dimethylphenyl)-6-methylheptyl]urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.77, 0.79, 0.81 (2d, 6H), 1.04-1.7 (c, 7H),2.18 (s, 3H), 2.23 (s, 3H), 2.31 (s, 3H), 2.44 (s, 3H), 2.48 (s, 3H),3.04 (c, 1H), 3.19 (m, 1H), 3.53 (p, 1H), 4.2 (b, 1H), 5.33 (s, 1H),6.53 (s, 1H), 6.84 (d and s, 2H), 6.92 (d, 1H).

EXAMPLE 110N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-5-phenylpentyl]urea

37% yield.

¹ H NMR (300 MHz, CDCl₃) δ1.26, 1.29, 1.31, 1.33 (2t, 6H), 1.41-1.82 (c,4H), 2.17 (s, 3H), 2.22 (s, 3H), 2.46 (s, 3H), 2.54 (c, 2H), 2.81 (q,2H), 3.0-3.24 [c and including q (3.08), total 4H], 3.52 (p, 1H), 4.2(b, 1H), 5.31 (s, 1H), 6.56 (s, 2H), 6.82 6.85 (s and d, 2H), 6.91 (d,1H), 7.08 (d, 2H), 7.15 (d, 1H), 7.23 (t, 2H).

EXAMPLE 111N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)octyl]urea

26% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.19 (c, 8H), 1.27, 1.29, 1.32,1.34 (2t, 6H), 1.54 (c, 1H), 1.67 (c, 1H), 2.18 (s, 3H), 2.23 (s, 3H),2.46 (s, 3H), 2.82 (q, 2H), 2.98-3.14 [c including t (3.08) total 3H],3.19 (m, 1H), 3.53 (p, 1H), 4.2 (b, 1H), 5.31 (s, 1H), 6.56 (s, 1H),6.83, 6.85 (s and d, 2H), 6.92 (d, 1H).

EXAMPLE 112N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-5-methylhexyl]urea

39% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79, 0.80, 0.81, 0.82 (2d, 6H), 0.92-1.18 (c,2H), 1.27, 1.29, 1.31, 1.34 (2t, 6H), 1.4-1.75 (c, 3H), 2.17 (s, 3H),2.23 (s, 3H), 2.46 (s, 3H), 2.82 (q, 2H), 2.93-3.13 [c including t(3.08), total 3H], 3.2 (m, 1H), 3.53 (p, 1H), 4.2 (b, 1H), 5.3 (s, 1H),6.56 (s, 1H), 6.83, 6.85 (d and s, 2H), 6.92 (d, 1H).

EXAMPLE 113N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2chlorobenzo[b]thiophen-3-yl)-6-methylheptyl]urea

19% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.73, 0.75, 0.76, 0.78 (2d, 6H), 1.01-1.42 [cand 2t (1.22, 1.23, 1.24, 1.25, 1.27, 1.28), total 10H], 1.41 (h, 1H),1.79 (c, 1H), 1.92 (c, 1H), 2,44 (s, 3H), 2.74 (c, 2H), 3.02 (q, 2H),3.48 (c, 2H), 3.8 (c, 1H), 4.26 (b, 1H), 5.3 (s, 1H), 6.5 (s, 1H), 7.29(m, 2H), 7.66 (m, 1H), 7.77 (c, 1H).

EXAMPLE 114N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2chlorobenzo[b]thiophen-3-yl)-5-methylhexyl]urea

35% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.75-1.3 [c including 2d (0.77, 0.78, 0.79,0.80, 6H), and 2t (1.22, 1.23, 1.24, 1.25, 1.27, 1.28, 6H), total 14H],1.47 (h, 1H), 1.75-1.2 (c, 2H), 2.44 (s, 3H), 2.75 (c, 2H), 3.02 (q,2H), 3.46 (c, 2H), 3.8 (c, 1H), 4.27 (b, 1H), 5.3 (s, 1H), 6.5 (s, 1H),7.3 (m, 2H), 7.66 (m, 1H), 7.77 (c, 1H).

EXAMPLE 115N-2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(5,6,7,8-tetrahydronaphth-1-yl)heptyl]urea

36% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.2 (c, 6H), 1.29, 1.31, 1.34(2t, 6H), 1.45-1.82 (c, 6H), 2,46 (s, 3H), 2.7 (c, 4H), 2.83 (q, 2H),3.03-3.28 (c including q (3.08), total 4H), 3.46 (p, 1H), 4.23 (b, 1H),5.3 (s, 1H), 6.58 (s, 1H), 6.85, 6.88, 6.91 (2d, 2H), 6.98 (t, 1H).

EXAMPLE 116N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)heptyl]urea

20% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.21 (c, 6H), 1.28, 1.30, 1.32,1.35 (2t, 6H), 1.6 (c, 2H), 2.33 (s, 6H), 2.45 (s, 3H), 2.61 (c, 1H),2.84 (q, 2H), 3.05-3.2 [c and q (3.1), total 3H], 3.56 (p, 1H), 4.2 (b,1H), 5.3 (s, 1H), 6.59 (s, 1H), 6.67 (s, 2H), 6.78 (s, 1H).

EXAMPLE 117N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]urea

51% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.79 (t, 3H), 1.04-1.32 [c including 2t (1.22,1.23, 1.24, 1.25, 1.27, 1.28), total 12H], 1.81, (c, 1H), 1.94 (c, 1H),2.44 (s, 3H), 2.76 (c, 2H), 3.02 (q, 2H), 3.48 (c, 2H), 3.8 (c, 1H),4.27 (b, 1H), 5.3 (s, 1H), 6.5 (c, 1H), 7.3 (m, 2H), 7.66 (m, 1H), 7.78(c, 1H).

EXAMPLE 118N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)octyl]urea

19% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.83 (t, 3H), 1.2 (c, 8H), 1.27, 1.30, 1.32,1.35 (2t, 6H), 1.45-1.72 (c, 2H), 2.22 (s, 6H), 2.45 (s, 3H), 2.6 (c,1H), 2.84 (q, 2H), 3.05-3.2 [c and q (3.1), total 3H], 3.56 (h, 1H),4.23 (b, 1H), 5.35 (s, 1H), 6.58 (s, 1H), 6.67 (s, 2H), 6.77 (s, 1H).

EXAMPLE 119N-[2,4-Bis(ethylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethyl-4-methoxyphenyl)heptyl]urea

50% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.2 (c, 6H), 1.26, 1.29, 1.31,1.34 (2t, 6H), 1.44-1.72 (c, 2H), 2.09 (s, 3H), 2.18 (s, 3H), 2.46 (s,3H), 2.82 (q, 2H), 3.96 (c, 1H), 3.01-3.2 [c including q (3.07), total3H], 3.48 (p, 1H), 3.78 (s, 3H), 4.18 (b, 1H), 5.29 (s, 1H), 6.48 (s,1H), 6.56 (s, 1H), 6.77 (s, 1H).

EXAMPLE 120N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea

10% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82 (t, 3H), 1.23 (c, 6H), 1.73 (c, 2H), 2.2(s, 3H), 2.41 (s, 3H), 2.46 (s, 6H), 3.25 (p, 1H), 3.5 (t, 2H), 4.28 (b,1H), 5.35 (s, 1H), 6.45 (s, 1H), 6.99 (s, 1H), 7.15 (d, 1H), 7.55 (s,1H), 7.7 (d, 1H).

EXAMPLE 121N-[2-(2-Chlorobenzo[b]thiophen-3-yl)-5-methylhexyl]-N'-(2,6-diisopropylphenyl)urea

43% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.72-1.31 (c, 20H), 1.46 (h, 1H), 1.78 (c,1H), 1.82 (c, 1H), 3.06, (c, 2H), 3.44 (c, 2H), 3.76 (c, 1H), 4.01 (b,1H), 5.52 (s, 1H), 7.06 (c, 2H), 7.26 (c, 3H), 7.64 (c, 1H), 7.71 (c,1H).

EXAMPLE 122N-(2,6-Diisopropylphenyl)-N'-[2-(5-methylbenzo[b]thiophen-3-yl)-5-methylhexyl]urea

44% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.76-1.3 [m, c including d (0.79, 0.81), total21H], 1.46 (h, 1H), 1.68 (c, 2H), 2.45 (s, 3H), 3.08 (c) and 3.17 (m),(total 2H), 3.47 (c, 2H), 4.08 (b, 1H), 5.57 (s, 1H), 6.86 (s, 1H), 7.05(s, 1H), 7.07 (s, 1H), 7.14 (d, 1H), 7.22 (d, 1H), 7.51 (s, 1H), 7.67(d, 1H).

EXAMPLE 123N-[2-(Benzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea

41% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.76-1.31 (c, 20H), 1.68 (c, 2H), 1.95 (c,1H), 3.05 (c, 2H), 3.25 (p, 1H), 3.49 (c, 2H), 4.1 (b, 1H), 5.72 (s,1H), 6.92 (s, 1H), 7.06 (s, 1H), 7.08 (s, 1H), 7.21-7.38 (c, 3H), 7.74(m, 1H), 7.8 (m, 1H).

EXAMPLE 124N-[2-(Benzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea

58% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.74-1.48 [m, c including 2d (0.76, 0.77,0.78, 0.80) total 22H], 1.67 (m, 2H), 1.8 (c, 1H), 3.07 (c, 2H), 3.25(p, 1H), 3.48 (c, 2H), 4.1 (b, 1H), 5.68 (s, 1H), 6.92 (s, 1H), 7.06 (s,1H), 7.08 (s, 1H), 7.2-7.4 (c, 3H), 7.74 (m, 1H), 7.8 (m, 1H).

EXAMPLE 125N-[2-(2-Chlorobenzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea

70% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.7-1.3 !c and 2d (0,73, 0.75, 0.76, 0.78),total 22H], 1.4 (h, 1H), 1.73 (c, 1H), 1.91 (c, 1H), 3.06 (c, 2H), 3.44(c, 2H), 3.76 (c, 1H), 4.02 (b, 1H), 5.54 (s, 1H), 7.06 (c, 2H),7.2-7.32 (c, 3H), 7.64 (m, 1H), 7.71 (c, 1H).

EXAMPLE 126N-(2,6-Diisopropylphenyl)-N'-[2-(5-Methylbenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]urea

70% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.8-1.3 (c, 12H), 1.51 (m, 2H), 1.78 (m, 2H),2.0 (m, 2H), 2.46 (s, 3H), 3.07 (c, 2H), 3.25 (p, 1H), 3.48 (m, 2H),4.11 (b, 1H), 5.6 (s, 1H), 6.92 (s, 1H), 7.07 (d, 2H), 7.16 (d, 1H),7.24 (d, 1H), 7.52 (s, 1H), 7.69 (d, 1H).

EXAMPLE 127

N-[2-(2-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]-N'-(2,6-diisopropylphenyl)urea

46% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.78-1.27 (c, 12H), 1.42 (c, 2H), 1.85 (c,1H), 2.02 (c, 3H), 3.08 (c, 2H), 3.47 (c, 2H), 3.79 (c, 1H), 4.08 (b,1H), 5.58 (s, 1H), 7.07 (d, 2H) 7.2-7.35 (c, 3H), 7.7 (c, 2H).

EXAMPLE 128N-(2,6-Diisopropylphenyl)-N'-[2-(naphth-2-yl)-6,6,6-trifluorohexyl]urea

67% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.63-1.14 (c, 12H), 1.45 (m, 2H), 1.68-2.08(c, 4H), 2.9 (c, 1H), 3.09 (c, 1H), 3.4 (c, 1H), 3.6 (c, 1H), 3.79 (c,1H), 4.07 (b, 1H), 5.67 (s, 1H), 7.02 (d, 2H), 7.2 (m, 2H), 7.34 (t,1H), 7.47 (m, 2H), 7.68 (d, 1H), 7.82 (m, 1H), 8.06 (c, 1H).

EXAMPLE 129N-[7,7-Difluoro-2-(naphth-1-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea

58% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.63-1.46 (c, 16H), 1.57-1.9 (c, 4H), 2.92 (c,1H), 3.08 (c, 1H), 3.39 (m, 1H), 3.59 (c, 1H), 3.75 (c, 1H), 4.03 (b,1H), 5.57 (s, 1H), 5.48 5.67, 5.86 (3t, total 1H), 7.0 (d, 1H), 7.18 (t,2H), 7.32 (t, 1H), 7.44 (m, 2H), 7.65 (d, 1H), 7.8 (m, 1H), 8.05 (m,1H).

EXAMPLE 130N-[7,7-difluoro-2-(2-chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea

73% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.73-1.5 (c, 16H), 1.56-1.85 (c, 3H), 1.96 (c,1H), 3.07 (c, 2H), 3.47 (c, 2H), 3.77 (c, 1H), 4.05 (b, 1H), 5.59 (s,1H), 5.50, 5.69, 5.88 (3t, total 1H), 7.06 (d, 2H), 7.2-7.35 (c, 3H),7.62-7.77 (c, 2H).

EXAMPLE 131N-[2-(5-Chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2,6-diisopropylphenyl)urea

59% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.77-1.46 (c, 21H), 1.65 (m, 2H), 3.01-3.24(m, 3H), 3.46 (m, 2H), 4.04 (b, 1H), 5.6 (s, 1H), 7.02 (s, 1H), 7.08 (c,2H), 7.2 (m, 2H), 7.71 (m, 2H).

EXAMPLE 132N-[2-(2-Chlorobenzo[b]thiophen-3-yl)heptyl]-N'-(2.6-diisopropylphenyl)urea

60% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.74-1.42 (c, 21H), 1.75 (c, 1H), 1.92 (c,1H), 3.07 (c, 2H), 3.45 (c, 2H), 3.76 (c, 1H), 4.02 (b, 1H), 5.74 (s,1H), 7.06 (c, 2H), 7.2-7.34 (m, 3H), 7.65 (m, 1H), 7.7 (c, 1H).

EXAMPLE 133N-[2-(5-Chlorobenzo[b]thiophen-3-yl)-6,6,6-trifluorohexyl]-N'-(2,6-diisopropylphenyl)urea

72% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.82-1.32 (c, 12H), 1.5 (m, 2H), 1.76 (c, 2H),2.0 (c, 2H), 3.07 (c, 2H), 3.23 (p, 1H), 3.48 (c, 2H), 4.11 (b, 1H),5.68 (s, 1H), 7.07, 7.09 (d and s, 3H), 7.21-7.34 (m, 2H), 7.72, 7.75 (dand s, 2H).

EXAMPLE 134N-(2,6-(Diisopropylphenyl)-N'-[2-(5-methylbenzo[b]thiophen-3-yl)heptyl]urea

50% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.76-1.32 (c, 21H), 1.67 (c, 2H), 2.45 (s,3H), 3.08 (c, 2H), 3.2 (p, 1H), 3.47 (t, 2H), 4.06 (b, 1H), 5.6 (s, 1H),6.86 (s, 1H), 7.07 (d, 2H), 7.14 (d, 1H), 7.22 (d, 1H), 7.52 (s, 1H),7.67 (d, 1H).

EXAMPLE 135N-[2-(5-Chlorobenzo[b]thiophen-3-yl)-6-methylheptyl]-N'-(2,6-diisopropylphenyl)urea

49% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.75-1.8 [c including 2d (0.76, 0.78, 0.79,0.80), total 23H), 2.26 (m, 2H), 3.07 (p, 2H), 3.18 (p, 1H), 3.47 (c,2H), 4.06 (b, 1H), 5.65 (s, 1H), 7.03 (s, 1H), 7.08 (c, 2H), 7.2-7.3 (m,2H), 7.71 (m, 2H).

EXAMPLE 136N-(2,6-(Diisopropylphenyl)-N'-[2-(2,5-dimethylphenyl)-6,6,6-trifluorohexyl]urea

37% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.9-1.76 (c, 16H), 1.98 (m, 2H), 2.08 (s, 3H),2.19 (s, 3H), 2.95-3.21 (c, 4H), 3.52 (p, 1H), 3.97 (b, 1H), 5.6 (b,1H), 6.74 (s, 1H), 6.83 (d, 1H), 6.9 (d, 1H), 7.11 (d, 2H), 7.28 (t,1H).

EXAMPLE 137N-[7,7-Difluoro-2-(2,5-dimethylphenyl)heptyl]-N'-(2,6-diisopropylphenyl)urea

65% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.92-1.82 (c, 20H), 2.06 (s, 3H), 2.18 (s,3H), 2.98 (c, 1H), 3.12 (c, 3H), 3.51 (p, 1H), 3.95 (b, 1H), 5.61 (s,1H), 5.52, 5.71, 5.9 (3t, total 1H), 6.74 (s, 1H), 6.81 (d, 1H), 6.89(d, 1H), 7.1 (d, 2H), 7.27 (t, 1H).

EXAMPLE 138 N-(2,6-Diisopropylphenyl)-N'-[2-(napth-1-yl)heptyl]urea

61% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.78 (t, 3H), 0.9-1.3 (m and c, 18H), 1.72 (c,2H), 2.85-3.16 (c, 2H), 3.41 (m, 1H), 3.58 (c, 1H), 3.72 (c, 1H), 4.02(b, 1H), 5.49 (s, 1H), 7.01 (d, 2H), 7.18 (m, 2H), 7.31 (t, 1H), 7.44(m, 2H), 7.65 (d, 1H), 7.8 (m, 1H), 8.07 (m, 1H).

EXAMPLE 139 N-(2,6-Diisopropylphenyl)-N'-[6-methyl-2-(napth-1-yl)heptyl]urea

59% yield.

¹ H NMR (300 MHz, CDCl₃) δ0.74 (t, 6H), 0.91-1.29 (m and c, 18H), 1.4(h, 1H), 1.7 (c, 2H), 2.84-3.16 (c, 2H), 3.41 (m, 1H), 3.51-3.8 (c, 2H),4.02 (c, 1H), 5.51 (s, 1H), 7.0 (d, 2H), 7.19 (m, 2H), 7.31 (t, 1H),7.44 (m, 2H), 7.66 (d, 1H), 8.07 (m, 1H).

I claim:
 1. A compound of the formula ##STR10## wherein Q is oxygen orsulfur R¹⁷ is --(CH₂)_(n) --CR¹⁹ R²⁰)_(z) (CH₂)_(r) --AR XXXVIIIwhereinn is 1; z is 1; and r is 0; R¹⁹ and R²⁰ are independently selected fromhydrogen, optionally halogenated (C₄ -C₁₂) alkyl, optionally substitutedaryl-(C₁ -C₅)alkyl, (C₃ -C₈)cycloalkyl-(C₁ -C₅)alkyl and Ar; or R¹⁹ andR²⁰ and the carbon to which they are attached form a (C₄ -C₇) cycloalkylring or a benzene-fused (C₅ -C₇) cycloalkyl or -heteroalkyl ring; withthe proviso that R¹⁹ and R²⁰ cannot both be hydrogen; Ar is selectedfrom the group consisting of ##STR11## wherein U is J, a direct bond,--CH═CH-- or --CH₂ CH₂ --; z, n and r are as defined above; x is aninteger from 3 to 10 and w is 0 or an integer from 1 to x-1; R²¹, R²²and each R²³ is independently selected from the group consisting ofoptionally halogenated (C₁ -C₆)alkyl, optionally halogenated (C₁-C₆)alkoxy, optionally halogenated (C₁ -C₆)alkylthio, phenyl andhalogen; wherein the alkyl groups in said alkyl, alkoxy and althylthiogroups may be straight chained or if comprising three or more carbonsmay be branched, cyclic or a combination of cyclic and branched orstraight chain moieties; or R²¹ and R²² together form a group of theformula

    --J(CH.sub.2).sub.t --J-- or --(CH.sub.2).sub.q --

wherein J is oxygen or sulfur; t is an integer from 1 to 3; and q is aninteger from 3 to 5; K is J-- or --CH═CH--; L is --(CH₂)_(u) or--(CH₂)_(v) J--; wherein J is as defined above; u is a n integer 3 to 5;and v is 2, 3 or 4; R¹⁸ is hydrogen, R¹ is ##STR12## wherein m is 0 oran integer from 1 to 4; y is 0 or 1; Each R⁶ is independently selectedfrom the group consisting of halogen, optionally halogenated (C₁-C₆)alkyl, optionally halogenated (C₁ -C₆)alkoxy, optionally halogenated(C₁ -C₆)alkylthio, (C₅ -C₇)cycloalkylthio, phenyl (C₁ -C₆)alkylthio,substituted phenylthio, heteroarylthio, heteroaryloxy, (C₁-C⁶)alkylsulfinyl, (C₁ -C₆)alkylsulfonyl, (C₅ -C₇)cycloalkylsulfinyl,(C₅ -C₇)cycloalkylsulfonyl, phenyl (C₁ -C₆)alkylsulfinyl, phenyl(C₁-C₆)alkylsulfonyl, substituted phenylsulfinyl, substitutedphenylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl, and NR¹⁰ R¹¹,wherein R¹⁰ and R¹¹ are the same or different and are selected from thegroup consisting of hydrogen, (C₁ -C₆)alkyl, phenyl, substituted phenyl,(C₁ -C₆)acyl, aroyl, and substituted aroyl, wherein said substitutedphenyl and substituted aroyl groups are substituted with one or moresubstituents independently selected from the group consisting of (C₁-C₆) alkyl, (C₁ -C₆) alkoxy, (C₁ -C₆) alkylthio, halogen andtrifluoromethyl, or R¹⁰ and R¹¹, together with the nitrogen to whichthey are attached, form a piperidine, pyrrolidine or morpholine ring;and G is carbon and the nitrogen may be oxidized; or a pharmaceuticallyacceptable salt of said compound.
 2. The compound according to claim 1wherein R¹ is ##STR13## and each R⁶ is independently selected from thegroup consisting of (C₁ -C₈)alkyl, and (C₁ -C₈)alkylthio, R¹⁷ isselected from the group consisting of benzenefused(C₅ -C₈) cycloalkyland optionally substituted (C₁ -C₈)alkyl wherein said substituents areselected from the group consisting of phenyl, biphenyl, fluorenyl,benzo[b]thiophenyl, naphthyl, halogen and (C₃ -C₁₂) cycloalkyl whereinsaid phenyl, naphthyl, cycloalkyl, biphenyl, fluorenyl andbenzo[b]thiophenyl groups are optionally substituted with substituentsselected from the group consisting of optionally halogenated (C₁-C₆)alkoxy, optionally halogenated (C₁ -C₆)alkyl, optionally halogenated(C₁ -C₆)alkylthio and halogen and R¹⁸ is hydrogen.
 3. A compoundaccording to claim 1, said compound being selected from the groupconsistingof:N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2,2-diphenylethyl]urea;N-[4,6-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(1-phenylcyclopentyl)methyl]urea;N-[4,6-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclopentyl)methyl}urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(1-phenylcyclohexyl)methyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[{1-(4-methylphenyl)cyclohexyl}methyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea;N-[2,4-Bis(isopropylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-phenyl)butyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-ethyl-2-{2-methylphenyl})butyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-phenyl-2-propyl)penty]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2-methylphenyl}-2-propyl)pentyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2-methylphenyl}-2-butyl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethoxyphenyl}-2-propyl)pentyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,3-dimethoxyphenyl}-2-propyl)pentyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethylphenyl}-2-propyl)pentyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2-methylphenyl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(4-methylphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)heptyl]urea;N-[2-(4-Bis(methylthio)-6-methylpyridin-3-yl-]-N'-[2-(2,5-dimethylphenyl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(2,5-dimethylphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl-}-N'-{2-(2,4-dimethylphenyl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(3-methylphenyl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(2,4-dimethylphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(naphth-1-yl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(naphth-2-yl)hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl}-N'-{2-(naphth-1-yl)hexyl]ureaN-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,3-dimethoxyphenyl)heptyl]-urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3-methylphenyl)octyl]urea;N-[2,4-Bis(methyl)-6-methylpyridin-3-yl]-N'-[2-(3,4,5-trimethoxyphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2,5-dimethyl-4-methoxyphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethoxyphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2-(3,5-dimethoxyphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-(2-(2,5-dimethoxyphenyl)octyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-2-[2-(3-methylphenyl)-6,6,6-trifluorohexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-{2,-(5-chlorobenzo[b]thiophen-3-yl)heptyl}ureaN-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(3,5-dimethylphenyl)heptyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)octyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[5-methyl-2-{3-methylphenyl}hexyl]urea;N-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[(2-{2,5-dimethylphenyl}-4-phenylbutyl]urea;andN-[2,4-Bis(methylthio)-6-methylpyridin-3-yl]-N'-[2-(2,5-dimethylphenyl)-5-phenylpentyl]urea.4. A pharmaceutical composition comprising an ACAT inhibiting effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable diluent or carrier.
 5. A method of inhibiting ACAT in a humanor animal comprising administering to said human or animal an ACATinhibiting amount of a compound according to claim 1.